TY  - JOUR
AB  - BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous clinical picture that is closely related to extracardiac comorbidities such as obesity, hypertension, and diabetes and is associated with chronic, low-grade systemic inflammation. Previous studies on myocardial biopsies of patients with HFpEF showed intramyocardial inflammatory activity, suggesting that the inflammatory processes in HFpEF are predominantly systemic and exhibit compartment-specific patterns. METHODS: We performed single-cell RNA sequencing of peripheral blood mononuclear cells of patients with HFpEF (n=6), heart failure with reduced ejection fraction patients (n=8), and healthy controls (n=7), taking obesity status into account. For validation, bulk RNA sequencing was performed on whole blood samples. In parallel, the systemic immune cell response was investigated in an HFpEF mouse model (induced by a high-fat diet plus L-NAME), with one group additionally administered the anti-inflammatory agent nitro-oleic acid. RESULTS: Analysis of human peripheral blood mononuclear cells revealed an HFpEF-specific inflammatory fingerprint, which manifested in obesity-related increased expression of cytokine signaling genes (eg, CCL2 and TNF) and obesity-independent increases in mitochondrial-associated activity. In the mouse model, HFpEF animals showed a comparable increase in inflammatory markers, with treatment with nitro-oleic acid leading to a partial normalization of immunologic signatures and a significant improvement in diastolic function. CONCLUSIONS: Our results demonstrate that the immune cells of patients with HFpEF are characterized by a distinct transcriptional immune signature that differs from that of patients with heart failure with reduced ejection fraction analyzed in this study. The conserved immunologic signatures between the human and murine data sets analyzed here, and the beneficial effect of nitro-oleic acid in the preclinical model induced by high-fat diet and L-NAME, provide translational insights and generate hypotheses for personalized interventions in HFpEF.
AU  - Kneuer, J.M.*
AU  - Müller, M.*
AU  - Erbe, S.*
AU  - Kokot, K.E.*
AU  - Rosch, S.*
AU  - Müller-Kozarez, I.*
AU  - Schrö, S.C.*
AU  - Maeder, C.*
AU  - Heitkamp, S.F.*
AU  - Gaul, S.*
AU  - von Haehling, S.*
AU  - Tönjes, A.*
AU  - Blüher, M.
AU  - Lurz, P.*
AU  - Wachter, R.*
AU  - Klinke, A.*
AU  - Laufs, U.*
AU  - Boeckel, J.N.*
C1  - 75236
C2  - 57867
CY  - Two Commerce Sq, 2001 Market St, Philadelphia, Pa 19103 Usa
SP  - 682-698
TI  - Circulating immune cell signature analysis in HFpEF across species.
JO  - Circ. Res.
VL  - 137
IS  - 5
PB  - Lippincott Williams & Wilkins
PY  - 2025
SN  - 0009-7330
ER  - 

TY  - JOUR
AB  - BACKGROUND: Tetraspanin CD151 is highly expressed in endothelia and reinforces cell adhesion, but its role in vascular inflammation remains largely unknown. METHODS: In vitro molecular and cellular biological analyses on genetically modified endothelial cells, in vivo vascular biological analyses on genetically engineered mouse models, and in silico systems biology and bioinformatics analyses on CD151-related events. RESULTS: Endothelial ablation of Cd151 leads to pulmonary and cardiac inflammation, severe sepsis, and perilous COVID-19, and endothelial CD151 becomes downregulated in inflammation. Mechanistically, CD151 restrains endothelial release of proinflammatory molecules for less leukocyte infiltration. At the subcellular level, CD151 determines the integrity of multivesicular bodies/lysosomes and confines the production of exosomes that carry cytokines such as ANGPT2 (angiopoietin-2) and proteases such as cathepsin-D. At the molecular level, CD151 docks VCP (valosin-containing protein)/p97, which controls protein quality via mediating deubiquitination for proteolytic degradation, onto endolysosomes to facilitate VCP/p97 function. At the endolysosome membrane, CD151 links VCP/p97 to (1) IFITM3, which regulates multivesicular body functions, to restrain IFITM3-mediated exosomal sorting, and (2) V-ATPase, which dictates endolysosome pH, to support functional assembly of V-ATPase. CONCLUSIONS: Distinct from its canonical function in strengthening cell adhesion at cell surface, CD151 maintains endolysosome function by sustaining VCP/p97-mediated protein unfolding and turnover. By supporting protein quality control and protein degradation, CD151 prevents proteins from (1) buildup in endolysosomes and (2) discharge through exosomes, to limit vascular inflammation. Also, our study conceptualizes that balance between degradation and discharge of proteins in endothelial cells determines vascular information. Thus, the IFITM3/V-ATPase-tetraspanin-VCP/p97 complexes on endolysosome, as a protein quality control and inflammation-inhibitory machinery, could be beneficial for therapeutic intervention against vascular inflammation.
AU  - Chen, J.*
AU  - Ding, Y.*
AU  - Jiang, C.*
AU  - Qu, R.*
AU  - Wren, J.D.*
AU  - Georgescu, C.*
AU  - Wang, X.*
AU  - Reuter, D.N.*
AU  - Liu, B.*
AU  - Giles, C.B.*
AU  - Mayr, C.
AU  - Schiller, H. B.
AU  - Dai, J.*
AU  - Stipp, C.S.*
AU  - Subramaniyan, B.*
AU  - Wang, J.*
AU  - Zuo, H.*
AU  - Huang, C.*
AU  - Fung, K.M.*
AU  - Rice, H.C.*
AU  - Sonnenberg, A.*
AU  - Wu, D.*
AU  - Walters, M.S.*
AU  - Zhao, Y.Y.*
AU  - Kanie, T.*
AU  - Hays, F.A.*
AU  - Papin, J.F.*
AU  - Wang, D.W.*
AU  - Zhang, X.A.*
C1  - 70364
C2  - 55532
SP  - 1330-1347
TI  - CD151 maintains endolysosomal protein quality to inhibit vascular inflammation.
JO  - Circ. Res.
VL  - 134
IS  - 10
PY  - 2024
SN  - 0009-7330
ER  - 

TY  - JOUR
AB  - Throughout our lifetime, each beat of the heart requires the coordinated action of multiple cardiac cell types. Understanding cardiac cell biology, its intricate microenvironments, and the mechanisms that govern their function in health and disease are crucial to designing novel therapeutical and behavioral interventions. Recent advances in single-cell and spatial omics technologies have significantly propelled this understanding, offering novel insights into the cellular diversity and function and the complex interactions of cardiac tissue. This review provides a comprehensive overview of the cellular landscape of the heart, bridging the gap between suspension-based and emerging in situ approaches, focusing on the experimental and computational challenges, comparative analyses of mouse and human cardiac systems, and the rising contextualization of cardiac cells within their niches. As we explore the heart at this unprecedented resolution, integrating insights from both mouse and human studies will pave the way for novel diagnostic tools and therapeutic interventions, ultimately improving outcomes for patients with cardiovascular diseases.
AU  - Palmer, J.A.*
AU  - Rosenthal, N.*
AU  - Teichmann, S.A.*
AU  - Litvinukova, M.
C1  - 70805
C2  - 55750
SP  - 1681-1702
TI  - Revisiting cardiac biology in the rra of single cell and spatial omics.
JO  - Circ. Res.
VL  - 134
IS  - 12
PY  - 2024
SN  - 0009-7330
ER  - 

TY  - JOUR
AB  - As global temperatures rise, extreme heat events are projected to become more frequent and intense. Extreme heat causes a wide range of health effects, including an overall increase in morbidity and mortality. It is important to note that while there is sufficient epidemiological evidence for heat-related increases in all-cause mortality, evidence on the association between heat and cause-specific deaths such as cardiovascular disease (CVD) mortality (and its more specific causes) is limited, with inconsistent findings. Existing systematic reviews and meta-analyses of epidemiological studies on heat and CVD mortality have summarized the available evidence. However, the target audience of such reviews is mainly limited to the specific field of environmental epidemiology. This overarching perspective aims to provide health professionals with a comprehensive overview of recent epidemiological evidence of how extreme heat is associated with CVD mortality. The rationale behind this broad perspective is that a better understanding of the effect of extreme heat on CVD mortality will help CVD health professionals optimize their plans to adapt to the changes brought about by climate change and heat events. To policymakers, this perspective would help formulate targeted mitigation, strengthen early warning systems, and develop better adaptation strategies. Despite the heterogeneity in evidence worldwide, due in part to different climatic conditions and population dynamics, there is a clear link between heat and CVD mortality. The risk has often been found to be higher in vulnerable subgroups, including older people, people with preexisting conditions, and the socioeconomically deprived. This perspective also highlights the lack of evidence from low- and middle-income countries and focuses on cause-specific CVD deaths. In addition, the perspective highlights the temporal changes in heat-related CVD deaths as well as the interactive effect of heat with other environmental factors and the potential biological pathways. Importantly, these various aspects of epidemiological studies have never been fully investigated and, therefore, the true extent of the impact of heat on CVD deaths remains largely unknown. Furthermore, this perspective also highlights the research gaps in epidemiological studies and the potential solutions to generate more robust evidence on the future consequences of heat on CVD deaths.
AU  - Singh, N.*
AU  - Areal, A.T.*
AU  - Breitner-Busch, S.
AU  - Zhang, S.*
AU  - Agewall, S.*
AU  - Schikowski, T.*
AU  - Schneider, A.E.
C1  - 70561
C2  - 55580
CY  - Two Commerce Sq, 2001 Market St, Philadelphia, Pa 19103 Usa
SP  - 1098-1112
TI  - Heat and cardiovascular mortality: An epidemiological perspective.
JO  - Circ. Res.
VL  - 134
IS  - 9
PB  - Lippincott Williams & Wilkins
PY  - 2024
SN  - 0009-7330
ER  - 

TY  - JOUR
AB  - Background: Circular RNAs (circRNAs) are generated by back-splicing of mostly mRNAs and are gaining increasing attention as a novel class of regulatory RNAs that control various cellular functions. However, their physiological roles and functional conservation in vivo are rarely addressed, given the inherent challenges of their genetic inactivation. Here we aimed to identify locus conserved circRNAs in mice and humans, which can be genetically deleted due to retained intronic elements not contained in the mRNA host gene to eventually address functional conservation. Methods: Mechanistically, we identified the protein syndesmos (SDOS) to specifically interact with cZNF292 in endothelial cells by RNA affinity purification and subsequent mass spectrometry analysis. Silencing of SDOS or its protein binding partner Syndecan-4, or mutation of the SDOS-cZNF292 binding site, prevented laminar flow-induced cytoskeletal reorganisation thereby recapitulating cZfp292 phenotypes. Results: Combining published endothelial RNA sequencing datasets with circRNAs of the circATLAS databank, we identified locus-conserved circRNA retaining intronic elements between mice and humans. CRISPR/Cas9 mediated genetic depletion of the top expressed circRNA cZfp292 resulted in an altered endothelial morphology and aberrant flow alignment in the aorta in vivo. Consistently, depletion of cZNF292 in endothelial cells in vitro abolished laminar flow-induced alterations in cell orientation, paxillin localisation and focal adhesion organisation. Conclusion: Together, our data reveal a hitherto unknown role of cZNF292/cZfp292 in endothelial flow responses, which influences endothelial shape.
AU  - Heumüller, A.W.*
AU  - Jones, A.
AU  - Mourao, A.
AU  - Klangwart, M.*
AU  - Shi, C.*
AU  - Wittig, I.*
AU  - Fischer, A.*
AU  - Muhly Reinholz, M.*
AU  - Buchmann, G.K.*
AU  - Dieterich, C.*
AU  - Potente, M.*
AU  - Braun, T.*
AU  - Grote, P.*
AU  - Jaé, N.*
AU  - Sattler, M.
AU  - Dimmeler, S.*
C1  - 63643
C2  - 51507
CY  - Two Commerce Sq, 2001 Market St, Philadelphia, Pa 19103 Usa
SP  - 67-79
TI  - Locus-conserved circular RNA cZNF292 controls endothelial cell flow responses.
JO  - Circ. Res.
VL  - 130
IS  - 1
PB  - Lippincott Williams & Wilkins
PY  - 2022
SN  - 0009-7330
ER  - 

TY  - JOUR
AB  - BACKGROUND: Despite mechanistic studies linking retinol and RBP4 (retinol binding protein 4) to the pathogenesis of cardiovascular diseases (CVD) and type 2 diabetes (T2D), epidemiological evidence is still conflicting. We investigated whether conflicting results of previous studies may be explained by differences in the association of retinol and RBP4 with cardiometabolic risk across subgroups with distinct sex, hypertension state, liver, or kidney function. METHODS: We used case-cohorts nested in the EPIC (European Prospective Investigation Into Cancer and Nutrition)-Potsdam cohort (n=27 548) comprising a random sample of participants (n=2500) and all physician-verified cases of incident CVD (n=508, median follow-up time 8.2 years) and T2D (n=820, median follow-up time 6.3 years). We estimated nonlinear and linear multivariable-adjusted associations between the biomarkers and cardiometabolic diseases by restricted cubic splines and Cox regression, respectively, testing potential interactions with hypertension, liver, and kidney function. Additionally, we performed 2-sample Mendelian Randomization analyses in publicly available data. RESULTS: The association of retinol with cardiometabolic risk was modified by hypertension state (P interaction CVD<0.001; P interaction T2D<0.001). Retinol was associated with lower cardiometabolic risk in participants with treated hypertension (hazard ratioper SD, 95% CI: CVD, 0.71 [0.56-0.90]; T2D, 0.81 [0.70-0.94]) but with higher cardiometabolic risk in normotensive participants (CVD, 1.32 [1.06-1.64]; T2D, 1.15 [0.98-1.36]). Our analyses also indicated a significant interaction between RBP4 and hypertension on CVD risk (P interaction=0.04). Regarding T2D risk, we observed a u-shaped association with RBP4 in women (P nonlinearity=0.01, P effect=0.02) and no statistically significant association in men. The biomarkers' interactions with liver or kidney function were not statistically significant. Hypertension state-specific associations for retinol concentrations with cardiovascular mortality risk were replicated in National Health and Nutrition Examination Survey III. CONCLUSIONS: Our findings suggest a hypertension-dependent relationship between plasma retinol and cardiometabolic risk and complex interactions of RBP4 with sex and hypertension on cardiometabolic risk.
AU  - Schiborn, C.*
AU  - Weber, D.*
AU  - Grune, T.*
AU  - Biemann, R.*
AU  - Jäger, S.*
AU  - Neu, N.*
AU  - Müller von Blumencron, M.*
AU  - Fritsche, A.
AU  - Weikert, C.*
AU  - Schulze, M.B.*
AU  - Wittenbecher, C.*
C1  - 65976
C2  - 53021
TI  - Retinol and retinol binding protein 4 levels and cardiometabolic disease risk.
JO  - Circ. Res.
VL  - 131
IS  - 7
PY  - 2022
SN  - 0009-7330
ER  - 

TY  - JOUR
AB  - Background: Dextro-transposition of the great arteries (D-TGA) is a severe congenital heart defect which affects approximately 1 in 4,000 live births. While there are several reports of D-TGA patients with rare variants in individual genes, the majority of D-TGA cases remain genetically elusive. Familial recurrence patterns and the observation that most cases with D-TGA are sporadic suggest a polygenic inheritance for the disorder, yet this remains unexplored. Methods: We sought to study the role of common single nucleotide polymorphisms (SNPs) in risk for D-TGA. We conducted a genome-wide association study in an international set of 1,237 patients with D-TGA and identified a genome-wide significant susceptibility locus on chromosome 3p14.3, which was subsequently replicated in an independent case-control set (rs56219800, meta-analysis P=8.6x10-10, OR=0.69 per C allele). Results: SNP-based heritability analysis showed that 25% of variance in susceptibility to D-TGA may be explained by common variants. A genome-wide polygenic risk score derived from the discovery set was significantly associated to D-TGA in the replication set (P=4x10-5). The genome-wide significant locus (3p14.3) co-localizes with a putative regulatory element that interacts with the promoter of WNT5A, which encodes the Wnt Family Member 5A protein known for its role in cardiac development in mice. We show that this element drives reporter gene activity in the developing heart of mice and zebrafish and is bound by the developmental transcription factor TBX20. We further demonstrate that TBX20 attenuates Wnt5a expression levels in the developing mouse heart. Conclusions: This work provides support for a polygenic architecture in D-TGA and identifies a susceptibility locus on chromosome 3p14.3 near WNT5A. Genomic and functional data support a causal role of WNT5A at the locus.
AU  - Skoric-Milosavljevic, D.*
AU  - Tadros, R.*
AU  - Bosada, F.M.*
AU  - Tessadori, F.*
AU  - van Weerd, J.H.*
AU  - Woudstra, O.I.*
AU  - Tjong, F.V.Y.*
AU  - Lahrouchi, N.*
AU  - Bajolle, F.*
AU  - Cordell, H.J.*
AU  - Agopian, A.J.*
AU  - Blue, G.M.*
AU  - Barge-Schaapveld, D.Q.*
AU  - Gewillig, M.H.*
AU  - Preuss, C.*
AU  - Lodder, E.M.*
AU  - Barnett, P.*
AU  - Ilgun, A.*
AU  - Beekman, L.*
AU  - van Duijvenboden, K.*
AU  - Bokenkamp, R.*
AU  - Müller-Nurasyid, M.
AU  - Vliegen, H.W.*
AU  - Konings, T.C.*
AU  - van Melle, J.P.*
AU  - van Dijk, A.*
AU  - van Kimmenade, R.R.*
AU  - Roos-Hesselink, J.W.*
AU  - Sieswerda, G.*
AU  - Meijboom, F.*
AU  - Abdul-Khaliq, H.*
AU  - Berger, F.*
AU  - Dittrich, S.*
AU  - Hitz, M.P.*
AU  - Moosmann, J.*
AU  - Riede, F.T.*
AU  - Schubert, S.*
AU  - Galan, P.*
AU  - Lathrop, G.M.*
AU  - Munter, H.M.*
AU  - Al-Chalabi, A.*
AU  - Shaw, C.E.*
AU  - Shaw, P.J.*
AU  - Morrison, K.E.*
AU  - Veldink, J.H.*
AU  - van den Berg, L.H.*
AU  - Evans, S.M.*
AU  - Nobrega, M.A.*
AU  - Aneas, I.*
AU  - Radivojkov-Blagojevic, M.
AU  - Meitinger, T.
AU  - Oechslin, E.*
AU  - Mondal, T.*
AU  - Bergin, M.L.*
AU  - Smythe, J.F.*
AU  - Altamirano-Diaz, L.*
AU  - Lougheed, J.*
AU  - Bouma, B.J.*
AU  - Chaix, M.A.*
AU  - Kline, J.*
AU  - Bassett, A.S.*
AU  - Andelfinger, G.*
AU  - van der Palen, R.L.*
AU  - Bouvagnet, P.*
AU  - Clur, S.B.*
AU  - Breckpot, J.*
AU  - Kerstjens-Frederikse, W.S.*
AU  - Winlaw, D.S.*
AU  - Bauer, U.*
AU  - Mital, S.*
AU  - Goldmuntz, E.*
AU  - Keavney, B.D.*
AU  - Bonnet, D.*
AU  - Mulder, B.J.*
AU  - Tanck, M.*
AU  - Bakkers, J.*
AU  - Christoffels, V.M.*
AU  - Boogerd, C.J.*
AU  - Postma, A.V.*
AU  - Bezzina, C.R.*
C1  - 63794
C2  - 51762
CY  - Two Commerce Sq, 2001 Market St, Philadelphia, Pa 19103 Usa
SP  - 166-180
TI  - Common genetic variants contribute to risk of transposition of the great arteries.
JO  - Circ. Res.
VL  - 130
IS  - 2
PB  - Lippincott Williams & Wilkins
PY  - 2021
SN  - 0009-7330
ER  - 

TY  - JOUR
AB  - Rationale:A reduced rate of myocardial infarction has been reported in patients with atrial fibrillation treated with FXa (factor Xa) inhibitors including rivaroxaban compared with vitamin K antagonists. At the same time, low-dose rivaroxaban has been shown to reduce mortality and atherothrombotic events in patients with coronary artery disease. Yet, the mechanisms underlying this reduction remain unknown.Objective:In this study, we hypothesized that rivaroxaban's antithrombotic potential is linked to a hitherto unknown rivaroxaban effect that impacts on platelet reactivity and arterial thrombosis.Methods and Results:In this study, we identified FXa as potent, direct agonist of the PAR-1 (protease-activated receptor 1), leading to platelet activation and thrombus formation, which can be inhibited by rivaroxaban. We found that rivaroxaban reduced arterial thrombus stability in a mouse model of arterial thrombosis using intravital microscopy. For in vitro studies, atrial fibrillation patients on permanent rivaroxaban treatment for stroke prevention, respective controls, and patients with new-onset atrial fibrillation before and after first intake of rivaroxaban (time series analysis) were recruited. Platelet aggregation responses, as well as thrombus formation under arterial flow conditions on collagen and atherosclerotic plaque material, were attenuated by rivaroxaban. We show that rivaroxaban's antiplatelet effect is plasma dependent but independent of thrombin and rivaroxaban's anticoagulatory capacity.Conclusions:Here, we identified FXa as potent platelet agonist that acts through PAR-1. Therefore, rivaroxaban exerts an antiplatelet effect that together with its well-known potent anticoagulatory capacity might lead to reduced frequency of atherothrombotic events and improved outcome in patients.
AU  - Petzold, T.*
AU  - Thienel, M.*
AU  - Dannenberg, L.K.*
AU  - Mourikis, P.*
AU  - Helten, C.*
AU  - Ayhan, A.*
AU  - M'Pembele, R.*
AU  - Achilles, A.*
AU  - Trojovsky, K.*
AU  - Konsek, D.*
AU  - Zang, Z.*
AU  - Regenauer, R.*
AU  - Pircher, J.*
AU  - Ehrlich, A.*
AU  - Lüsebrink, E.*
AU  - Nicolai, L.*
AU  - Stocker, T.*
AU  - Brandl, R.*
AU  - Röschentaler, F.*
AU  - Strecker, J.*
AU  - Saleh, I.*
AU  - Spannagl, M.*
AU  - Mayr, C.
AU  - Schiller, H. B.
AU  - Jung, C.*
AU  - Gerdes, N.*
AU  - Hoffmann, T.*
AU  - Levkau, B.*
AU  - Hohlfeld, T.*
AU  - Zeus, T.*
AU  - Schulz, C.*
AU  - Kelm, M.*
AU  - Polzin, A.*
C1  - 58193
C2  - 48067
CY  - Two Commerce Sq, 2001 Market St, Philadelphia, Pa 19103 Usa
SP  - 486-500
TI  - Rivaroxaban reduces arterial thrombosis by inhibition of FXa driven platelet activation via protease activated receptor-1.
JO  - Circ. Res.
VL  - 126
IS  - 4
PB  - Lippincott Williams & Wilkins
PY  - 2020
SN  - 0009-7330
ER  - 

TY  - JOUR
AU  - Petzold, T.*
AU  - Thienel, M.*
AU  - Dannenberg, L.*
AU  - Mourikis, P.*
AU  - Helten, C.*
AU  - Ayhan, A.*
AU  - M'Pembele, R.*
AU  - Achilles, A.*
AU  - Trojovky, K.*
AU  - Zhang, Z.*
AU  - Regenauer, R.*
AU  - Pircher, J.*
AU  - Ehrlich, A.*
AU  - Lüsebrink, E.*
AU  - Nicolai, L.*
AU  - Stocker, T.J.*
AU  - Brandl, R.*
AU  - Röschenthaler, F.*
AU  - Strecker, J.*
AU  - Saleh, I.*
AU  - Spannagl, M.*
AU  - Mayr, C.
AU  - Schiller, H. B.
AU  - Jung, C.*
AU  - Gerdes, N.*
AU  - Hoffmann, T.*
AU  - Levkau, B.*
AU  - Hohlfeld, T.*
AU  - Zeus, T.*
AU  - Schulz, C.*
AU  - Kelm, M.*
AU  - Polzin, A.*
C1  - 59005
C2  - 48480
CY  - Two Commerce Sq, 2001 Market St, Philadelphia, Pa 19103 Usa
SP  - E54-E55
TI  - Response by Petzold et al to letter regarding article, "Rivaroxaban reduces arterial thrombosis by inhibition of FXa-driven platelet activation via protease activated receptor-1".
JO  - Circ. Res.
VL  - 126
IS  - 8
PB  - Lippincott Williams & Wilkins
PY  - 2020
SN  - 0009-7330
ER  - 

TY  - JOUR
AB  - Rationale:Longitudinal studies are required to distinguish within versus between-individual variation and repeatability of gene expression. They are uniquely positioned to decipher genetic signal from environmental noise, with potential application to gene variant and expression studies. However, longitudinal analyses of gene expression in healthy individuals-especially with regards to alternative splicing-are lacking for most primary cell types, including platelets.Objective:To assess repeatability of gene expression and splicing in platelets and use repeatability to identify novel platelet expression quantitative trait loci (QTLs) and splice QTLs.Methods and Results:We sequenced the transcriptome of platelets isolated repeatedly up to 4 years from healthy individuals. We examined within and between individual variation and repeatability of platelet RNA expression and exon skipping, a readily measured alternative splicing event. We find that platelet gene expression is generally stable between and within-individuals over time-with the exception of a subset of genes enriched for the inflammation gene ontology. We show an enrichment among repeatable genes for associations with heritable traits, including known and novel platelet expression QTLs. Several exon skipping events were also highly repeatable, suggesting heritable patterns of splicing in platelets. One of the most repeatable was exon 14 skipping of SELP. Accordingly, we identify rs6128 as a platelet splice QTL and define an rs6128-dependent association between SELP exon 14 skipping and race. In vitro experiments demonstrate that this single nucleotide variant directly affects exon 14 skipping and changes the ratio of transmembrane versus soluble P-selectin protein production.Conclusions:We conclude that the platelet transcriptome is generally stable over 4 years. We demonstrate the use of repeatability of gene expression and splicing to identify novel platelet expression QTLs and splice QTLs. rs6128 is a platelet splice QTL that alters SELP exon 14 skipping and soluble versus transmembrane P-selectin protein production.
AU  - Rondina, M.T.*
AU  - Voora, D.*
AU  - Simon, L.
AU  - Schwertz, H.*
AU  - Harper, J.F.*
AU  - Lee, O.*
AU  - Bhatlekar, S.C.*
AU  - Li, Q.*
AU  - Eustes, A.S.*
AU  - Montenont, E.*
AU  - Campbell, R.A.*
AU  - Tolley, N.D.*
AU  - Kosaka, Y.*
AU  - Weyrich, A.S.*
AU  - Bray, P.F.*
AU  - Rowley, J.W.*
C1  - 58585
C2  - 48498
CY  - Two Commerce Sq, 2001 Market St, Philadelphia, Pa 19103 Usa
SP  - 501-516
TI  - Longitudinal RNA-Seq analysis of the reeatability of gene expression and splicing in human platelets identifies a platelet SELP splice QTL.
JO  - Circ. Res.
VL  - 126
IS  - 4
PB  - Lippincott Williams & Wilkins
PY  - 2020
SN  - 0009-7330
ER  - 

TY  - JOUR
AB  - Rationale: Proinflammatory cytokines have been identified as potential targets for lowering vascular risk. Experimental evidence and Mendelian randomization suggest a role of MCP-1 (monocyte chemoattractant protein-1) in atherosclerosis and stroke. However, data from large-scale observational studies are lacking. Objective: To determine whether circulating levels of MCP-1 are associated with risk of incident stroke in the general population. Methods and Results: We used previously unpublished data on 17 180 stroke-free individuals (mean age, 56.7 +/- 8.1 years; 48.8% men) from 6 population-based prospective cohort studies and explored associations between baseline circulating MCP-1 levels and risk of any stroke, ischemic stroke, and hemorrhagic stroke during a mean follow-up interval of 16.3 years (280 522 person-years at risk; 1435 incident stroke events). We applied Cox proportional-hazards models and pooled hazard ratios (HRs) using random-effects meta-analyses. After adjustments for age, sex, race, and vascular risk factors, higher MCP-1 levels were associated with increased risk of any stroke (HR per 1-SD increment in ln-transformed MCP-1, 1.07; 95% CI, 1.01-1.14). Focusing on stroke subtypes, we found a significant association between baseline MCP-1 levels and higher risk of ischemic stroke (HR, 1.11 [1.02-1.21]) but not hemorrhagic stroke (HR, 1.02 [0.82-1.29]). The results followed a dose-response pattern with a higher risk of ischemic stroke among individuals in the upper quartiles of MCP-1 levels as compared with the first quartile (HRs, second quartile: 1.19 [1.00-1.42]; third quartile: 1.35 [1.14-1.59]; fourth quartile: 1.38 [1.07-1.77]). There was no indication for heterogeneity across studies, and in a subsample of 4 studies (12 516 individuals), the risk estimates were stable after additional adjustments for circulating levels of IL (interleukin)-6 and high-sensitivity CRP (C-reactive protein). Conclusions: Higher circulating levels of MCP-1 are associated with increased long-term risk of stroke. Our findings along with genetic and experimental evidence suggest that MCP-1 signaling might represent a therapeutic target to lower stroke risk.Visual Overview: An online visual overview is available for this article.
AU  - Georgakis, M.K.*
AU  - Malik, R.*
AU  - Björkbacka, H.*
AU  - Pana, T.A.*
AU  - Demissie, S.*
AU  - Ayers, C.*
AU  - Elhadad, M.A.
AU  - Fornage, M.*
AU  - Beiser, A.S.*
AU  - Benjamin, E.J.*
AU  - Boekholdt, M.S.*
AU  - Engström, G.*
AU  - Herder, C.*
AU  - Hoogeveen, R.C.*
AU  - Koenig, W.*
AU  - Melander, O.*
AU  - Orho-Melander, M.*
AU  - Schiopu, A.*
AU  - Söderholm, M.*
AU  - Wareham, N.*
AU  - Ballantyne, C.M.*
AU  - Peters, A.
AU  - Seshadri, S.*
AU  - Myint, P.K.*
AU  - Nilsson, J.*
AU  - de Lemos, J.A.*
AU  - Dichgans, M.*
C1  - 57007
C2  - 47468
CY  - Two Commerce Sq, 2001 Market St, Philadelphia, Pa 19103 Usa
SP  - 773-782
TI  - Circulating monocyte chemoattractant protein-1 and risk of stroke meta-analysis of population-based studies involving 17 180 individuals.
JO  - Circ. Res.
VL  - 125
IS  - 8
PB  - Lippincott Williams & Wilkins
PY  - 2019
SN  - 0009-7330
ER  - 

TY  - JOUR
AB  - Rationale: COMMD (copper metabolism MURR1 domain)-containing proteins are a part of the CCC (COMMD-CCDC22 [coiled-coil domain containing 22]-CCDC93 [coiled-coil domain containing 93]) complex facilitating endosomal traffcking of cell surface receptors. Hepatic COMMD1 inactivation decreases CCDC22 and CCDC93 protein levels, impairs the recycling of the LDLR (low-density lipoprotein receptor), and increases plasma lowdensity lipoprotein cholesterol levels in mice. However, whether any of the other COMMD members function similarly as COMMD1 and whether perturbation in the CCC complex promotes atherogenesis remain unclear. Objective: The main aim of this study is to unravel the contribution of evolutionarily conserved COMMD proteins to plasma lipoprotein levels and atherogenesis. Methods and Results: Using liver-specifc Commd1, Commd6, or Commd9 knockout mice, we investigated the relation between the COMMD proteins in the regulation of plasma cholesterol levels. Combining biochemical and quantitative targeted proteomic approaches, we found that hepatic COMMD1, COMMD6, or COMMD9 defciency resulted in massive reduction in the protein levels of all 10 COMMDs. This decrease in COMMD protein levels coincided with destabilizing of the core (CCDC22, CCDC93, and chromosome 16 open reading frame 62 [C16orf62]) of the CCC complex, reduced cell surface levels of LDLR and LRP1 (LDLR-related protein 1), followed by increased plasma low-density lipoprotein cholesterol levels. To assess the direct contribution of the CCC core in the regulation of plasma cholesterol levels, Ccdc22 was deleted in mouse livers via CRISPR/Cas9-mediated somatic gene editing. CCDC22 defciency also destabilized the complete CCC complex and resulted in elevated plasma low-density lipoprotein cholesterol levels. Finally, we found that hepatic disruption of the CCC complex exacerbates dyslipidemia and atherosclerosis in ApoE3∗Leiden mice. Conclusions: Collectively, these fndings demonstrate a strong interrelationship between COMMD proteins and the core of the CCC complex in endosomal LDLR traffcking. Hepatic disruption of either of these CCC components causes hypercholesterolemia and exacerbates atherosclerosis. Our results indicate that not only COMMD1 but all other COMMDs and CCC components may be potential targets for modulating plasma lipid levels in humans.
AU  - Fedoseienko, A.*
AU  - Wijers, M.*
AU  - Wolters, J.C.*
AU  - Dekker, D.*
AU  - Smit, M.*
AU  - Huijkman, N.*
AU  - Kloosterhuis, N.*
AU  - Klug, H.*
AU  - Schepers, A.
AU  - van Dijk, K.W.*
AU  - Levels, J.H.M.*
AU  - Billadeau, D.D.*
AU  - Hofker, M.H.*
AU  - Van Deursen, J.*
AU  - Westerterp, M.*
AU  - Burstein, E.*
AU  - Kuivenhoven, J.A.*
AU  - Van De Sluis, B.*
C1  - 54183
C2  - 45435
SP  - 1648-1660
TI  - The COMMD family regulates plasma LDL levels and attenuates atherosclerosis through stabilizing the CCC complex in endosomal LDLR traffcking.
JO  - Circ. Res.
VL  - 122
IS  - 12
PY  - 2018
SN  - 0009-7330
ER  - 

TY  - JOUR
AB  - Rationale: Coronary artery disease (CAD) is a critical determinant of morbidity and mortality. Previous studies have identified several cardiovascular disease risk factors, which may partly arise from a shared genetic basis with CAD, and thus be useful for discovery of CAD genes. Objective: We aimed to improve discovery of CAD genes and inform the pathogenic relationship between CAD and several cardiovascular disease risk factors using a shared polygenic signal-informed statistical framework. Methods and Results: Using genome-wide association studies summary statistics and shared polygenic pleiotropy-informed conditional and conjunctional false discovery rate methodology, we systematically investigated genetic overlap between CAD and 8 traits related to cardiovascular disease risk factors: low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, type 2 diabetes mellitus, C-reactive protein, body mass index, systolic blood pressure, and type 1 diabetes mellitus. We found significant enrichment of single-nucleotide polymorphisms associated with CAD as a function of their association with low-density lipoprotein, high-density lipoprotein, triglycerides, type 2 diabetes mellitus, C-reactive protein, body mass index, systolic blood pressure, and type 1 diabetes mellitus. Applying the conditional false discovery rate method to the enriched phenotypes, we identified 67 novel loci associated with CAD (overall conditional false discovery rate <0.01). Furthermore, we identified 53 loci with significant effects in both CAD and at least 1 of low-density lipoprotein, high-density lipoprotein, triglycerides, type 2 diabetes mellitus, C-reactive protein, systolic blood pressure, and type 1 diabetes mellitus. Conclusions: The observed polygenic overlap between CAD and cardiometabolic risk factors indicates a pathogenic relation that warrants further investigation. The new gene loci identified implicate novel genetic mechanisms related to CAD.
AU  - LeBlanc, M.*
AU  - Zuber, V.*
AU  - Andreassen, B.K.*
AU  - Witoelar, A.W.*
AU  - Zeng, L.*
AU  - Bettella, F.*
AU  - Wang, Y.*
AU  - McEvoy, L.K.*
AU  - Thompson, W.K.*
AU  - Schork, A.J.*
AU  - Reppe, S.*
AU  - Barrett-Connor, E.*
AU  - Ligthart, S.*
AU  - Dehghan, A.*
AU  - Gautvik, K.M.*
AU  - Nelson, C.P.*
AU  - Schunkert, H.*
AU  - Samani, N.J.*
AU  - CARDIoGRAM Consortium (Döring, A.
AU  - Klopp, N.)
AU  - Ridker, P.M.*
AU  - Chasman, D.I.*
AU  - Aukrust, P.*
AU  - Djurovic, S.*
AU  - Frigessi, A.*
AU  - Desikan, R.S.*
AU  - Dale, A.M.*
AU  - Andreassen, O.A.*
C1  - 47901
C2  - 41412
CY  - Philadelphia
SP  - 83-94
TI  - Identifying novel gene variants in coronary artery disease and shared genes with several cardiovascular risk factors.
JO  - Circ. Res.
VL  - 118
IS  - 1
PB  - Lippincott Williams & Wilkins
PY  - 2016
SN  - 0009-7330
ER  - 

TY  - JOUR
AB  - RATIONALE: Semaphorin 3A (SEMA3A)-encoded semaphorin is a chemorepellent that disrupts neural patterning in the nervous and cardiac systems. In addition, SEMA3A has an amino acid motif that is analogous to hanatoxin, an inhibitor of voltage-gated K channels. SEMA3A-knockout mice exhibit an abnormal ECG pattern and are prone to ventricular arrhythmias and sudden cardiac death. OBJECTIVE:: Our aim was to determine whether SEMA3A is a naturally occurring protein inhibitor of Kv4.3 (Ito) channels and its potential contribution to Brugada syndrome. METHODS AND RESULTS:: Kv4.3, Nav1.5, Cav1.2, or Kv4.2 were coexpressed or perfused with SEMA3A in HEK293 cells, and electrophysiological properties were examined via whole-cell patch clamp technique. SEMA3A selectively altered Kv4.3 by significantly reducing peak current density without perturbing Kv4.3 cell surface protein expression. SEMA3A also reduced Ito current density in cardiomyocytes derived from human-induced pluripotent stem cells. Disruption of a putative toxin binding domain on Kv4.3 was used to assess physical interactions between SEMA3A and Kv4.3. These findings in combination with coimmunoprecipitations of SEMA3A and Kv4.3 revealed a potential direct binding interaction between these proteins. Comprehensive mutational analysis of SEMA3A was performed on 198 unrelated SCN5A genotype-negative patients with Brugada syndrome, and 2 rare SEMA3A missense mutations were identified. The SEMA3A mutations disrupted SEMA3A's ability to inhibit Kv4.3 channels, resulting in a significant gain of Kv4.3 current compared with wild-type SEMA3A. CONCLUSIONS:: This study is the first to demonstrate SEMA3A as a naturally occurring protein that selectively inhibits Kv4.3 and SEMA3A as a possible Brugada syndrome susceptibility gene through a Kv4.3 gain-of-function mechanism.
AU  - Boczek, N.J.*
AU  - Ye, D.*
AU  - Johnson, E.K.*
AU  - Wang, W.*
AU  - Crotti, L.
AU  - Tester, D.J.*
AU  - Dagradi, F.*
AU  - Mizusawa, Y.*
AU  - Torchio, M.*
AU  - Alders, M.*
AU  - Giudicessi, J.R.*
AU  - Wilde, A.A.M.*
AU  - Schwartz, P.J.*
AU  - Nerbonne, J.M.*
AU  - Ackerman, M.J.*
C1  - 31909
C2  - 34870
CY  - Philadelphia
SP  - 460-469
TI  - Characterization of SEMA3A-encoded semaphorin as a naturally occurring Kv4.3 protein inhibitor and its contribution to Brugada syndrome.
JO  - Circ. Res.
VL  - 115
IS  - 4
PB  - Lippincott Williams & Wilkins
PY  - 2014
SN  - 0009-7330
ER  - 

TY  - JOUR
AB  - Rationale: 22q11 deletion syndrome arises from recombination between low-copy repeats on chromosome 22. Typical deletions result in hemizygosity for TBX1 associated with congenital cardiovascular disease. Deletions distal to the typically deleted region result in a similar cardiac phenotype but lack in extracardiac features of the syndrome, suggesting that a second haploinsufficient gene maps to this interval. Objective: The transcription factor HIC2 is lost in most distal deletions, as well as in a minority of typical deletions. We used mouse models to test the hypothesis that HIC2 hemizygosity causes congenital heart disease. Methods and Results: We created a genetrap mouse allele of Hic2. The genetrap reporter was expressed in the heart throughout the key stages of cardiac morphogenesis. Homozygosity for the genetrap allele was embryonic lethal before embryonic day E10.5, whereas the heterozygous condition exhibited a partially penetrant late lethality. One third of heterozygous embryos had a cardiac phenotype. MRI demonstrated a ventricular septal defect with over-riding aorta. Conditional targeting indicated a requirement for Hic2 within the Nkx2.5+ and Mesp1+ cardiovascular progenitor lineages. Microarray analysis revealed increased expression of Bmp10. Conclusions: Our results demonstrate a novel role for Hic2 in cardiac development. Hic2 is the first gene within the distal 22q11 interval to have a demonstrated haploinsufficient cardiac phenotype in mice. Together our data suggest that HIC2 haploinsufficiency likely contributes to the cardiac defects seen in distal 22q11 deletion syndrome.
AU  - Dykes, I.M.*
AU  - van Bueren, K.L.*
AU  - Ashmore, R.J.*
AU  - Floß, T.
AU  - Wurst, W.
AU  - Szumska, D.*
AU  - Bhattacharya, S.*
AU  - Scambler, P.J.*
C1  - 31737
C2  - 34703
CY  - Philadelphia
SP  - 23-31
TI  - HIC2 is a novel dosage-dependent regulator of cardiac development located within the distal 22q11 deletion syndrome region.
JO  - Circ. Res.
VL  - 115
IS  - 1
PB  - Lippincott Williams & Wilkins
PY  - 2014
SN  - 0009-7330
ER  - 

TY  - JOUR
AB  - Tertiary lymphoid organs emerge in tissues in response to nonresolving inflammation. Recent research characterized artery tertiary lymphoid organs in the aorta adventitia of aged apolipoprotein E-deficient mice. The atherosclerosis-associated lymphocyte aggregates are organized into distinct compartments, including separate T-cell areas harboring conventional, monocyte-derived, lymphoid, and plasmacytoid dendritic cells, as well as activated T-cell effectors and memory cells; B-cell follicles containing follicular dendritic cells in activated germinal centers; and peripheral niches of plasma cells. Artery tertiary lymphoid organs show marked neoangiogenesis, aberrant lymphangiogenesis, and extensive induction of high endothelial venules. Moreover, newly formed lymph node-like conduits connect the external lamina with high endothelial venules in T-cell areas and also extend into germinal centers. Mouse artery tertiary lymphoid organs recruit large numbers of naïve T cells and harbor lymphocyte subsets with opposing activities, including CD4(+) and CD8(+) effector and memory T cells, natural and induced CD4(+) regulatory T cells, and memory B cells at different stages of differentiation. These data suggest that artery tertiary lymphoid organs participate in primary immune responses and organize T- and B-cell autoimmune responses in advanced atherosclerosis. In this review, we discuss the novel concept that pro- and antiatherogenic immune responses toward unknown arterial wall-derived autoantigens may be organized by artery tertiary lymphoid organs and that disruption of the balance between pro- and antiatherogenic immune cell subsets may trigger clinically overt atherosclerosis.
AU  - Mohanta, S.K.*
AU  - Yin, C.*
AU  - Peng, L.*
AU  - Srikakulapu, P.*
AU  - Bontha, V.*
AU  - Hu, D.
AU  - Weih, F.*
AU  - Weber, C.*
AU  - Gerdes, N.*
AU  - Habenicht, A.J.R.*
C1  - 31371
C2  - 34495
CY  - Philadelphia
SP  - 1772-1787
TI  - Artery tertiary lymphoid organs contribute to innate and adaptive immune responses in advanced mouse atherosclerosis.
JO  - Circ. Res.
VL  - 114
IS  - 11
PB  - Lippincott Williams & Wilkins
PY  - 2014
SN  - 0009-7330
ER  - 

TY  - JOUR
AB  - Rationale: Growing evidence indicates that oxidative stress contributes markedly to endothelial dysfunction. The selenoenzyme glutathione peroxidase 4 (Gpx4) is an intracellular antioxidant enzyme important for the protection of membranes by its unique activity to reduce complex hydroperoxides in membrane bilayers and lipoprotein particles. Yet a role of Gpx4 in endothelial cell function has remained enigmatic. Objective: To investigate the role of Gpx4 ablation and subsequent lipid peroxidation in the vascular compartment in vivo. Methods and Results: Endothelial-specific deletion of Gpx4 had no obvious impact on normal vascular homeostasis nor did it impair tumor-derived angiogenesis in mice maintained on a normal diet. By stark contrast, aortic explants from endothelial-specific Gpx4 knockout mice showed a markedly reduced number of endothelial branches in sprouting assays. To shed light onto this apparent discrepancy between the in vivo and ex vivo results, we depleted mice of a second antioxidant, vitamin E, which is normally absent under ex vivo conditions. Mice were therefore fed a vitamin E-depleted diet for 6 weeks before endothelial deletion of Gpx4 was induced by 4-hydroxytamoxifen. Surprisingly, about 80% of the knockout mice died. Histopathological analysis revealed detachment of endothelial cells from the basement membrane as well as endothelial cell death in multiple organs which triggered thrombus formation. Thromboembolic events were the likely cause of various clinical pathologies including heart failure, renal and splenic micro-infarctions or paraplegia. Conclusions: Here we show for the first time that in the absence of Gpx4, sufficient vitamin E supplementation is crucial for endothelial viability.
AU  - Wortmann, M.*
AU  - Schneider, M.*
AU  - Pircher, J.*
AU  - Hellfritsch, J.*
AU  - Aichler, M.
AU  - Vegi, N.*
AU  - Koelle, P.*
AU  - Kuhlencordt, P.*
AU  - Walch, A.K.
AU  - Pohl, U.*
AU  - Bornkamm, G.W.
AU  - Conrad, M.
AU  - Beck, H.*
C1  - 24921
C2  - 31717
SP  - 408-417
TI  - Combined deficiency in glutathione peroxidase 4 and vitamin E causes multi-organ thrombus formation and early death in mice.
JO  - Circ. Res.
VL  - 113
IS  - 4
PB  - Lippincott Williams & Wilkins
PY  - 2013
SN  - 0009-7330
ER  - 

TY  - JOUR
AB  - Telethonin (also known as titin-cap or t-cap) is a 19-kDa Z-disk protein with a unique β-sheet structure, hypothesized to assemble in a palindromic way with the N-terminal portion of titin and to constitute a signalosome participating in the process of cardiomechanosensing. In addition, a variety of telethonin mutations are associated with the development of several different diseases; however, little is known about the underlying molecular mechanisms and telethonin's in vivo function. Here we aim to investigate the role of telethonin in vivo and to identify molecular mechanisms underlying disease as a result of ist mutation. By using a variety of different genetically altered animal models and biophysical experiments we show that contrary to previous views, telethonin is not an indispensable component of the titin-anchoring system, nor is deletion of the gene or cardiac specific overexpression associated with a spontaneous cardiac phenotype. Rather, additional titin-anchorage sites, such as actin-titin cross-links via α-actinin, are sufficient to maintain Z-disk stability despite the loss of telethonin. We demonstrate that a main novel function of telethonin is to modulate the turnover of the proapoptotic tumor suppressor p53 after biomechanical stress in the nuclear compartment, thus linking telethonin, a protein well known to be present at the Z-disk, directly to apoptosis ("mechanoptosis"). In addition, loss of telethonin mRNA and nuclear accumulation of this protein is associated with human heart failure, an effect that may contribute to enhanced rates of apoptosis found in these hearts. Telethonin knockout mice do not reveal defective heart development or heart function under basal conditions, but develop heart failure following biomechanical stress, owing at least in part to apoptosis of cardiomyocytes, an effect that may also play a role in human heart failure.
AU  - Knöll, R.*
AU  - Linke, W.A.*
AU  - Zou, P.
AU  - Miocic, S.*
AU  - Kostin, S.*
AU  - Buyandelger, B.*
AU  - Ku, C.H.*
AU  - Neef, S.*
AU  - Bug, M.*
AU  - Schäfer, K.*
AU  - Knöll, G.*
AU  - Felkin, L.E.*
AU  - Wessels, J.*
AU  - Toischer, K.*
AU  - Hagn, F.*
AU  - Kessler, H.*
AU  - Didié, M.*
AU  - Quentin, T.*
AU  - Maier, L.S.*
AU  - Teucher, N.*
AU  - Unsöld, B.*
AU  - Schmidt, A.*
AU  - Birks, E.J.*
AU  - Gunkel, S.*
AU  - Lang, P.*
AU  - Granzier, H.*
AU  - Zimmermann, W.H.*
AU  - Field, L.J.*
AU  - Faulkner, G.*
AU  - Dobbelstein, M.*
AU  - Barton, PJ.*
AU  - Sattler, M.
AU  - Wilmanns, M.*
AU  - Chien, K.R.
C1  - 6630
C2  - 29009
CY  - Baltimore, MD, USA
SP  - 758-769
TI  - Telethonin deficiency is associated with maladaptation to biomechanical stress in the mammalian heart.
JO  - Circ. Res.
VL  - 109
IS  - 7
PB  - Lippincott Williams & Wilkins
PY  - 2011
SN  - 0009-7330
ER  - 

TY  - JOUR
AB  - In atherosclerosis, circulating platelets interact with endothelial cells and monocytes, leading to cell activation and enhanced recruitment of leukocytes into the vascular wall. The invasion of monocytes is accompanied by overexpression of matrix metalloproteinases (MMPs), which are thought to promote atherosclerosis and trigger plaque rupture. Following interaction with itself, the extracellular matrix metalloproteinase inducer (EMMPRIN) induces MMP synthesis via a little-known intracellular pathway. Recently, we showed upregulation of EMMPRIN on monocytes during acute myocardial infarction. EMMPRIN also stimulates secretion of MMP-9 by monocytes and of MMP-2 by smooth muscle cells, indicating that it may be an important regulator of MMP activity. Expression of EMMPRIN on platelets has not been described until now. Here, we demonstrate that resting platelets show low surface expression of EMMPRIN, which is upregulated by various platelet stimulators (flow cytometry). EMMPRIN is located in the open canalicular system and in alpha granules of platelets (according to electron microscopy and sucrose gradient ultracentrifugation). Platelet stimulation with recombinant EMMPRIN-Fc induced surface expression of CD40L and P-selectin (according to flow cytometry), suggesting that EMMPRIN-EMMPRIN interaction activates platelets. Coincubation of platelets with monocytes induced EMMPRIN-mediated nuclear factor kappaB activation (according to Western blot) in monocytes with increased MMP-9 (zymography), interleukin-6, and tumor necrosis factor-alpha secretion (according to ELISA) by monocytes. In conclusion, EMMPRIN displays a new platelet receptor that is upregulated on activated platelets. Binding of EMMPRIN to platelets fosters platelet degranulation. Platelet-monocyte interactions via EMMPRIN stimulate nuclear factor kappaB-driven inflammatory pathways in monocytes, such as MMP and cytokine induction. Thus, EMMPRIN may represent a novel target to diminish the burden of protease activity and inflammation in atherosclerosis.
AU  - Schmidt, R.*
AU  - Bültmann, A.*
AU  - Fischel, S.*
AU  - Gillitzer, A.*
AU  - Cullen, P.*
AU  - Walch, A.K.
AU  - Jost, P.*
AU  - Ungerer, M.*
AU  - Tolley, N.D.*
AU  - Lindemann, S.*
AU  - Gawaz, M.*
AU  - Schömig, A.*
AU  - May, A.E.*
C1  - 4122
C2  - 25768
SP  - 302-309
TI  - Extracellular matrix metalloproteinase inducer (CD147) is a novel receptor on platelets, activates platelets, and augments nuclear factor kappaB-dependent inflammation in monocytes.
JO  - Circ. Res.
VL  - 102
IS  - 3
PB  - Lippincott Williams & Wilkins
PY  - 2008
SN  - 0009-7330
ER  - 

TY  - JOUR
AB  - Circulating progenitor cells home to sites of postnatal neovascularization and differentiate into endothelial cells but questions remain regarding the source of these cells. Indeed, a recent study suggests that nonbone marrow-derived cells may be even more important than bone marrow-derived cells in the setting of transplant arteriosclerosis. Thus, we aimed to thoroughly investigate the contribution of nonbone marrow-derived progenitor cells for neovascularization. We exclusively identified nonbone marrow-derived progenitor cells by combining a parabiosis model with reverse bone marrow transplantation followed by hindlimb ischemia. In this model, nonbone marrow-derived circulating progenitor cells attributed for 74+/-13% of the circulating progenitor cells that incorporated into the ischemic hindlimb. Increasing evidence suggests that organs such as small intestine and liver contain a considerable number of tissue resident progenitor cells and, thus, represent putative sources for nonbone marrow-derived progenitors. To track organ-derived progenitors, we transplanted sex-mismatched small intestine or liver, respectively, into rats followed by induction of hindlimb ischemia. These experiments show that organ-derived progenitor cells are contributing to postnatal vasculogenesis (intestine: 4.7+/-3.7%; liver: 6.3+/-2.2%). Based on the subsequent observation that liver-derived nonhematopoietic c-kit(+)CD45(-) progenitors are mobilized on induction of hindlimb ischemia, we prospectively isolated and intravenously infused these progenitors from murine livers. The isolated cells demonstrated a marked capacity for enhancing neovascularization and restoring blood flow to the ischemic hindlimb (no cells: 26.4+/-4.8% of normal blood flow; c-kit(+)CD45(-) cells: 67.0+/-8.0% of normal flow; P<0.01). In conclusion, we find that nonbone marrow-derived c-kit(+)CD45(-) progenitors contribute to postnatal neovascularization to an extent that is similar to that of bone marrow-derived progenitor cells. Intestine and liver represent a rich source for mobilized tissue-residing progenitor cells.
AU  - Aicher, A.*
AU  - Rentsch, M.*
AU  - Sasaki, K.*
AU  - Ellwart, J.W.
AU  - Fändrich, F.*
AU  - Siebert, R.*
AU  - Cooke, J.P.*
AU  - Dimmeler, S.*
AU  - Heeschen, C.*
C1  - 4168
C2  - 24799
SP  - 581-589
TI  - Nonbone marrow-derived circulating progenitor cells contribute to postnatal neovascularization following tissue ischemia.
JO  - Circ. Res.
VL  - 100
IS  - 4
PB  - Lippincott Williams & Wilkins
PY  - 2007
SN  - 0009-7330
ER  - 

TY  - JOUR
AB  - Stress-dependent regulation of cardiac action potential duration is mediated by the sympathetic nervous system and the hypothalamic-pituitary-adrenal axis. It is accompanied by an increased magnitude of the slow outward potassium ion current, I(Ks). KCNQ1 and KCNE1 subunits coassemble to form the I(Ks) channel. Mutations in either subunit cause long QT syndrome, an inherited cardiac arrhythmia associated with an increased risk of sudden cardiac death. Here we demonstrate that exocytosis of KCNQ1 proteins to the plasma membrane requires the small GTPase RAB11, whereas endocytosis is dependent on RAB5. We further demonstrate that RAB-dependent KCNQ1/KCNE1 exocytosis is enhanced by the serum- and glucocorticoid-inducible kinase 1, and requires phosphorylation and activation of phosphoinositide 3-phosphate 5-kinase and the generation of PI(3,5)P(2). Identification of KCNQ1/KCNE1 recycling and its modulation by serum- and glucocorticoid-inducible kinase 1-phosphoinositide 3-phosphate 5-kinase -PI(3,5)P(2) provides a mechanistic insight into stress-induced acceleration of cardiac repolarization.
AU  - Seebohm, G.*
AU  - Strutz-Seebohm, N.*
AU  - Birkin, R.*
AU  - Dell, G.*
AU  - Bucci, C.*
AU  - Spinosa, M.R.*
AU  - Baltaev, R.*
AU  - Mack, A.F.*
AU  - Korniychuk, G.*
AU  - Choudhury, A.*
AU  - Marks, D.*
AU  - Pagano, R.E.*
AU  - Attali, B.*
AU  - Pfeufer, A.
AU  - Kass, RS.*
AU  - Sanguinetti, M.C.*
AU  - Tavare, J.M.*
AU  - Lang, F.*
C1  - 4520
C2  - 24710
SP  - 686-692
TI  - Regulation of endocytic recycling of KCNQ1/KCNE1 potassium channels.
JO  - Circ. Res.
VL  - 100
IS  - 5
PB  - Lippincott Williams & Wilkins
PY  - 2007
SN  - 0009-7330
ER  - 

TY  - JOUR
AB  - Altered myocardial repolarization is one of the important substrates of ventricular tachycardia and fibrillation. The influence of rare gene variants on repolarization is evident in familial long QT syndrome. To investigate the influence of common gene variants on the QT interval we performed a linkage disequilibrium based SNP association study of four candidate genes. Using a two-step design we analyzed 174 SNPs from the KCNQ1, KCNH2, KCNE1, and KCNE2 genes in 689 individuals from the population-based KORA study and 14 SNPs with results suggestive of association in a confirmatory sample of 3277 individuals from the same survey. We detected association to a gene variant in intron 1 of the KCNQ1 gene (rs757092, +1.7 ms/allele, P=0.0002) and observed weaker association to a variant upstream of the KCNE1 gene (rs727957, +1.2 ms/allele, P=0.0051). In addition we detected association to two SNPs in the KCNH2 gene, the previously described K897T variant (rs1805123, −1.9 ms/allele, P=0.0006) and a gene variant that tags a different haplotype in the same block (rs3815459, +1.7 ms/allele, P=0.0004). The analysis of additive effects by an allelic score explained a 10.5 ms difference in corrected QT interval length between extreme score groups and 0.95% of trait variance (P<0.00005). These results confirm previous heritability studies indicating that repolarization is a complex trait with a significant heritable component and demonstrate that high-resolution SNP-mapping in large population samples can detect and fine map quantitative trait loci even if locus specific heritabilities are small.
AU  - Pfeufer, A.
AU  - Jalilzadeh, S.
AU  - Perz, S.
AU  - Mueller, J.C.
AU  - Hinterseer, M.*
AU  - Illig, T.
AU  - Akyol, M.*
AU  - Huth, C.
AU  - Schöpfer-Wendels, A.
AU  - Kuch, B.*
AU  - Steinbeck, G.*
C1  - 4066
C2  - 22706
SP  - 693-701
TI  - Common variants in myocardial ion channel genes modify the QT interval in the general population: Results from the KORA study.
JO  - Circ. Res.
VL  - 96
PY  - 2005
SN  - 0009-7330
ER  -