TY  - JOUR
AB  - BACKGROUND: Using data from the largest German cohort study, we aimed to investigate sex differences in the relationship of socioeconomic position (SEP) with cardiovascular disease (CVD), CVD risk factors, and estimated CVD risk. METHODS AND RESULTS: A total of 204 780 (50.5% women) participants from the baseline examination of the population-based NAKO (German National Cohort) were included. Logistic, multinomial, and linear regression models were used to estimate sex-specific odds ratios (ORs) and β coefficients with 95% CIs of CVD, CVD risk factors, and very high-risk score (Systemic Coronary Risk Estimation-2) for CVD associated with SEP. Women-to-men ratios of ORs (RORs) with 95% CIs were estimated. In women compared with men, low versus high SEP (educational attainment and relative income) was more strongly associated with myocardial infarction, hypertension, obesity, overweight, elevated blood pressure, antihypertensive medication, and current alcohol consumption, but less strongly with current and former smoking. In women with the lowest versus highest educational level, the OR for a very high 10-year CVD risk was 3.61 (95% CI, 2.88-4.53) compared with 1.72 (95% CI, 1.51-1.96) in men. The women-to-men ROR was 2.33 (95% CI, 1.78-3.05). For the comparison of low versus high relative income, the odds of having a very high 10-year CVD risk was 2.55 (95% CI, 2.04-3.18) in women and 2.25 (95% CI, 2.08-2.42) in men (women-to-men ROR, 1.31 [95% CI, 1.05-1.63]). CONCLUSIONS: In women and men, there was an inverse relationship between indicators of SEP and the likelihood of having several CVD risk factors and a very high 10-year CVD risk. This association was stronger in women, suggesting that CVD risk is more strongly influenced by SEP in women compared with men.
AU  - Moreno Velásquez, I.*
AU  - Peters, S.A.E.*
AU  - Dragano, N.*
AU  - Greiser, K.H.*
AU  - Dörr, M.*
AU  - Fischer, B.*
AU  - Berger, K.*
AU  - Hannemann, A.*
AU  - Schnabel, R.B.*
AU  - Nauck, M.*
AU  - Göttlicher, S.
AU  - Rospleszcz, S.
AU  - Willich, S.N.*
AU  - Krist, L.*
AU  - Schulze, M.B.*
AU  - Günther, K.*
AU  - Brand, T.*
AU  - Schikowski, T.*
AU  - Emmel, C.*
AU  - Schmidt, B.*
AU  - Michels, K.B.*
AU  - Mikolajczyk, R.*
AU  - Kluttig, A.*
AU  - Harth, V.*
AU  - Obi, N.*
AU  - Castell, S.*
AU  - Klett-Tammen, C.J.*
AU  - Lieb, W.*
AU  - Becher, H.*
AU  - Winkler, V.*
AU  - Minnerup, H.*
AU  - Karch, A.*
AU  - Meinke-Franze, C.*
AU  - Leitzmann, M.*
AU  - Stein, M.J.*
AU  - Bohn, B.*
AU  - Schöttker, B.*
AU  - Trares, K.*
AU  - Peters, A.
AU  - Pischon, T.*
C1  - 73480
C2  - 56869
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
TI  - Sex differences in the relationship of socioeconomic position with cardiovascular disease, cardiovascular risk factors, and estimated cardiovascular disease risk: Results of the German National Cohort.
JO  - J. Am. Heart Assoc.
VL  - 14
IS  - 5
PB  - Wiley
PY  - 2025
ER  - 

TY  - JOUR
AB  - BACKGROUND: We sought to investigate the association between circulating inflammatory and cardiovascular proteomics biomarkers and cardiac autonomic nervous dysfunction-sensitive heart rate variability indices. METHODS: Using the population-based KORA (Cooperative Health Research in the Region of Augsburg) cohort, 233 proteomics biomarkers were quantified in baseline plasma samples of 1389 individuals using proximity extension assay technology. Five heart rate variability indices (Rényi entropy of the histogram with order [α] 4, total power of the density spectra, SD of word sequence, SD of the short-term normal-to-normal interval variability, compression entropy) were assessed at baseline in 982 individuals and in 407 individuals at baseline and at 14-year follow-up. Three unbiased multivariable selection models followed by linear or linear mixed-effects models with multiple testing correction were used to determine the association between proteomics biomarkers and heart rate variability indices. RESULTS: C-C motif chemokine 23 was positively associated, while peptidoglycan recognition protein nd fibroblast growth factor 21 were negatively associated with Rényi entropy of the histogram with order (α) 4 cross-sectionally. Tumor necrosis factor-related activation-induced cytokine and growth/differentiation factor 15 were negatively associated with compression entropy cross-sectionally. Over time, interleukin-6 receptor subunit α and macrophage colony-stimulating factor were positively and negatively associated with total power of the density spectra, respectively. Additionally, myoglobin and agouti-related protein were positively and negatively associated with SD of the short-term normal-to-normal interval variability, respectively. Gastrotropin and agouti-related protein were positively and negatively associated with compression entropy, respectively. CONCLUSIONS: This study identified novel circulating proteins associated with heart rate variability indices. These proteins could improve our understanding of the pathophysiology underlying cardiac autonomic nervous dysfunction.
AU  - Oluwagbemigun, K.*
AU  - Ziegler, D.*
AU  - Strom, A.*
AU  - Heier, M.
AU  - Bönhof, G.J.*
AU  - Roden, M.*
AU  - Rathmann, W.*
AU  - Meisinger, C.*
AU  - Peters, A.
AU  - Hauck, S.M.
AU  - Petrera, A.
AU  - Sinner, M.F.*
AU  - Kääb, S.*
AU  - Thorand, B.
AU  - Herder, C.*
C1  - 75475
C2  - 58168
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
TI  - Association of inflammatory and cardiovascular proteomics biomarkers with indices of heart rate variability in the general population: KORA S4/FF4 study.
JO  - J. Am. Heart Assoc.
VL  - 14
IS  - 18
PB  - Wiley
PY  - 2025
ER  - 

TY  - JOUR
AB  - BACKGROUND: Ventricular repolarization time (ECG QT and JT intervals) is associated with malignant arrhythmia. Genome-wide association studies have identified 230 independent loci for QT and JT; however, 50% of their heritability remains unexplained. Previous work supports a causal effect of lower serum calcium concentrations on longer ventricular repolarization time. We hypothesized calcium interactions with QT and JT variant associations could explain a proportion of the missing heritability. METHODS AND RESULTS: We performed genome-wide calcium interaction analyses for QT and JT intervals. Participants were stratified by their calcium level relative to the study distribution (top or bottom 20%). We performed a 2-stage analysis (genome-wide discovery [N=62 532] and replication [N=59 861] of lead variants) and a single-stage genome-wide meta-analysis (N=122 393, [European ancestry N=117 581, African ancestry N=4812]). We also calculated 2-degrees of freedom joint main and interaction and 1-degree of freedom interaction P values. In 2-stage and single-stage analyses, 50 and 98 independent loci, respectively, were associated with either QT or JT intervals (2-degrees of freedom joint main and interaction P value <5×10-8). No lead variant had a significant interaction result after correcting for multiple testing and sensitivity analyses provided similar findings. Two loci in the single-stage meta-analysis were not reported previously (SPPL2B and RFX6). CONCLUSIONS: We have found limited support for an interaction effect of serum calcium on QT and JT variant associations despite sample sizes with suitable power to detect relevant effects. Therefore, such effects are unlikely to explain a meaningful proportion of the heritability of QT and JT, and factors including rare variation and other environmental interactions need to be considered.
AU  - Young, W.J.*
AU  - van der Most, P.J.*
AU  - Bartz, T.M.*
AU  - Bos, M.M.*
AU  - Biino, G.*
AU  - Duong, T.*
AU  - Foco, L.*
AU  - Lominchar, J.T.*
AU  - Müller-Nurasyid, M.
AU  - Nardone, G.G.*
AU  - Pecori, A.*
AU  - Ramirez, J.*
AU  - Repetto, L.*
AU  - Schramm, K.
AU  - Shen, X.*
AU  - Van Duijvenboden, S.*
AU  - van Heemst, D.*
AU  - Weiss, S.*
AU  - Yao, J.*
AU  - Benjamins, J.W.*
AU  - Alonso, A.*
AU  - Spedicati, B.*
AU  - Biggs, M.L.*
AU  - Brody, J.A.*
AU  - Dörr, M.*
AU  - Fuchsberger, C.*
AU  - Gögele, M.*
AU  - Guo, X.*
AU  - Ikram, M.A.*
AU  - Jukema, J.W.*
AU  - Kääb, S.*
AU  - Kanters, J.K.*
AU  - Lin, H.J.*
AU  - Linneberg, A.*
AU  - Nauck, M.*
AU  - Nolte, I.M.*
AU  - Pianigiani, G.*
AU  - Santin, A.*
AU  - Soliman, E.Z.*
AU  - Tesolin, P.*
AU  - Vaccargiu, S.*
AU  - Waldenberger, M.
AU  - van der Harst, P.*
AU  - Verweij, N.*
AU  - Arking, D.E.*
AU  - Concas, M.P.*
AU  - de Grandi, A.*
AU  - Girotto, G.*
AU  - Grarup, N.*
AU  - Kavousi, M.*
AU  - Mook-Kanamori, D.O.*
AU  - Navarro, P.*
AU  - Orini, M.*
AU  - Padmanabhan, S.*
AU  - Pattaro, C.*
AU  - Peters, A.
AU  - Pirastu, M.*
AU  - Pramstaller, P.P.*
AU  - Heckbert, S.R.*
AU  - Sinner, M.*
AU  - Snieder, H.*
AU  - Völker, U.*
AU  - Wilson, J.F.*
AU  - Gauderman, W.J.*
AU  - Lambiase, P.D.*
AU  - Sotoodehnia, N.*
AU  - Tinker, A.*
AU  - Warren, H.R.*
AU  - Noordam, R.*
AU  - Munroe, P.B.*
C1  - 71554
C2  - 56304
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
TI  - Genome-wide interaction analyses of serum calcium on ventricular repolarization time in 125 393 participants.
JO  - J. Am. Heart Assoc.
VL  - 13
IS  - 17
PB  - Wiley
PY  - 2024
ER  - 

TY  - JOUR
AB  - Background Waist circumference and hip circumference are both strongly associated with risk of death; however, their joint association has rarely been investigated.Methods and Results The MONICA Risk, Genetics, Archiving, and Monograph (MORGAM) Project was conducted in 30 cohorts from 11 countries; 90 487 men and women, aged 30 to 74 years, predominantly white, with no history of cardiovascular disease, were recruited in 1986 to 2010 and followed up for up to 24 years. Hazard ratios were estimated using sex-specific Cox models, stratified by cohort, with age as the time scale. Models included baseline categorical obesity measures, age, total and high-density lipoprotein cholesterol, systolic blood pressure, antihypertensive drugs, smoking, and diabetes mellitus. A total of 9105 all-cause deaths were recorded during a median follow-up of 10 years. Hazard ratios for all-cause death presented J- or U-shaped associations with most obesity measures. With waist and hip circumference included in the same model, for all hip sizes, having a smaller waist was strongly associated with lower risk of death, except for men with the smallest hips. In addition, among those with smaller waists, hip size was strongly negatively associated with risk of death, with approximate to 20% more people identified as being at increased risk compared with waist circumference alone.Conclusions A more complex relationship between hip circumference, waist circumference, and risk of death is revealed when both measures are considered simultaneously. This is particularly true for individuals with smaller waists, where having larger hips was protective. Considering both waist and hip circumference in the clinical setting could help to best identify those at increased risk of death.
AU  - Cameron, A.J.*
AU  - Romaniuk, H.*
AU  - Orellana, L.*
AU  - Dallongeville, J.*
AU  - Dobson, A.J.*
AU  - Drygas, W.*
AU  - Ferrario, M.*
AU  - Ferrieres, J.*
AU  - Giampaoli, S.*
AU  - Gianfagna, F.*
AU  - Iacoviello, L.*
AU  - Jousilahti, P.*
AU  - Kee, F.*
AU  - Moitry, M.*
AU  - Niiranen, T.J.*
AU  - Pająk, A.*
AU  - Palmieri, L.*
AU  - Palosaari, T.*
AU  - Satu, M.*
AU  - Tamosiunas, A.*
AU  - Thorand, B.
AU  - Toft, U.*
AU  - Vanuzzo, D.*
AU  - Veikko, S.*
AU  - Veronesi, G.*
AU  - Wilsgaard, T.*
AU  - Kuulasmaa, K.*
AU  - Söderberg, S.*
C1  - 59550
C2  - 48835
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
TI  - Combined influence of waist and hip circumference on risk of death in a large cohort of European and Australian adults.
JO  - J. Am. Heart Assoc.
VL  - 9
IS  - 13
PB  - Wiley
PY  - 2020
ER  - 

TY  - JOUR
AB  - Background Electrocardiographic ( ECG ) parameters are regarded as intermediate phenotypes of cardiac arrhythmias. Insight into the genetic underpinnings of these parameters is expected to contribute to the understanding of cardiac arrhythmia mechanisms. Here we used HXB / BXH recombinant inbred rat strains to uncover genetic loci and candidate genes modulating ECG parameters. Methods and Results RR interval, PR interval, QRS duration, and QT c interval were measured from ECG s obtained in 6 male rats from each of the 29 available HXB / BXH recombinant inbred strains. Genes at loci displaying significant quantitative trait loci (QTL) effects were prioritized by assessing the presence of protein-altering variants, and by assessment of cis expression QTL ( eQTL ) effects and correlation of transcript abundance to the respective trait in the heart. Cardiac RNA -seq data were additionally used to generate gene co-expression networks. QTL analysis of ECG parameters identified 2 QTL for PR interval, respectively, on chromosomes 10 and 17. At the chromosome 10 QTL , cis- eQTL effects were identified for Acbd4, Cd300lg, Fam171a2, and Arhgap27; the transcript abundance in the heart of these 4 genes was correlated with PR interval. At the chromosome 17 QTL , a cis- eQTL was uncovered for Nhlrc1 candidate gene; the transcript abundance of this gene was also correlated with PR interval. Co-expression analysis furthermore identified 50 gene networks, 6 of which were correlated with PR interval or QRS duration, both parameters of cardiac conduction. Conclusions These newly identified genetic loci and gene networks associated with the ECG parameters of cardiac conduction provide a starting point for future studies with the potential of identifying novel mechanisms underlying cardiac electrical function.
AU  - Adriaens, M.E.*
AU  - Lodder, E.M.*
AU  - Moreno-Moral, A.*
AU  - Silhavý, J.*
AU  - Heinig, M.
AU  - Glinge, C.*
AU  - Belterman, C.*
AU  - Wolswinkel, R.*
AU  - Petretto, E.*
AU  - Pravenec, M.*
AU  - Remme, C.A.*
AU  - Bezzina, C.R.*
C1  - 54795
C2  - 45837
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
TI  - Systems genetics approaches in rat identify novel genes and gene networks associated with cardiac conduction.
JO  - J. Am. Heart Assoc.
VL  - 7
IS  - 21
PB  - Wiley
PY  - 2018
ER  - 

TY  - JOUR
AB  - Background-During treatment with direct oral anticoagulants (DOAC), coagulation assessment is required before thrombolysis, surgery, and if anticoagulation reversal is evaluated. Limited data support the accuracy of DOAC-specific coagulation assays around the current safe-for-treatment threshold of 30 ng/mL.Methods and Results-In 481 samples obtained from 96 patients enrolled at a single center, DOAC concentrations were measured using Hemoclot direct thrombin inhibitor assay, Biophen direct thrombin inhibitor assay or ecarin clotting time for dabigatran, chromogenic anti-Xa assay (AXA) for factor Xa inhibitors (rivaroxaban, apixaban) and ultraperformance liquid chromatography-tandem mass spectrometry as reference. All dabigatran-specific assays had high sensitivity to concentrations > 30 ng/mL, but specificity was lower for Hemoclot direct thrombin inhibitor assay (78.2%) than for Biophen direct thrombin inhibitor assay (98.9%) and ecarin clotting time (94.6%). AXA provided high sensitivity and specificity for rivaroxaban, but low sensitivity for apixaban (73.8%; concentrations up to 82 ng/mL were misclassified as < 30 ng/mL). If no DOAC-specific calibration for AXA is available, results 2-fold above the upper limit of normal indicate relevant rivaroxaban concentrations. For apixaban, all elevated results should raise suspicion of relevant anticoagulation.Conclusions-DOAC-specific tests differ considerably in diagnostic performance for concentrations close to the currently accepted safe-for-treatment threshold. Compared with Biophen direct thrombin inhibitor assay and ecarin clotting time, limited specificity of Hemoclot direct thrombin inhibitor assay poses a high risk of unnecessary anticoagulation reversal or treatment delays in patients on dabigatran. While AXA accurately detected rivaroxaban, the impact of low apixaban levels on the assay was weak. Hence, AXA results need to be interpreted with extreme caution when used to assess hemostatic function in patients on apixaban.
AU  - Ebner, M.*
AU  - Birschmann, I.*
AU  - Peter, A.
AU  - Härtig, F.*
AU  - Spencer, C.*
AU  - Kuhn, J.*
AU  - Rupp, A.*
AU  - Blumenstock, G.*
AU  - Zuern, C.S.*
AU  - Ziemann, U.*
AU  - Poli, S.*
C1  - 54641
C2  - 45735
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
TI  - Limitations of specific coagulation rests for direct oral anticoagulants: A critical analysis.
JO  - J. Am. Heart Assoc.
VL  - 7
IS  - 19
PB  - Wiley
PY  - 2018
ER  - 

TY  - JOUR
AB  - Background-Brain-derived neurotrophic factor (BDNF) is a pleiotropic peptide involved in maintaining endothelial integrity. It is unknown if circulating BDNF levels are associated with risk of cardiovascular disease (CVD). Methods and Results-We prospectively investigated the association of circulating BDNF levels with cardiovascular events and mortality in 3687 participants (mean age 65 years, 2068 women) from the Framingham Heart Study (FHS). Using a common nonsynonomous single nucleotide polymorphism (SNP) in the BDNF gene (rs6265), we then performed a Mendelian randomization experiment in the CARDIoGRAM (Coronary ARtery DIsease Genome-Wide Replication And Meta-Analysis) consortium (> 22 000 coronary artery disease [CAD] cases, > 60 000 controls) to investigate whether SNP rs6265 was associated with CAD in CARDIoGRAM and, if so, whether the effect estimate differed from that predicted based on FHS data. On follow-up (median 8.9 years), 467 individuals (261 women) in FHS experienced a CVD event, and 835 (430 women) died. In multivariable-adjusted Cox regression, serum BDNF was associated inversely with CVD risk (hazard ratio [HR] per 1-SD increase 0.88, 95% CI 0.80 to 0.97, P=0.01) and with mortality (HR 0.87, 95% CI 0.80 to 0.93, P=0.0002). SNP rs6265 was associated with BDNF concentrations (0.772 ng/mL increase per minor allele copy) in FHS. In CARDIoGRAM, SNP rs6265 was associated with CAD (odds ratio 0.957, 95% CI 0.923 to 0.992), a magnitude consistent with the predicted effect (HR per minor allele copy 0.99, 95% CI 0.98 to 1.0; P=0.06 for difference between predicted and observed effect). Conclusion-Higher serum BDNF is associated with a decreased risk of CVD and mortality. Mendelian randomization suggests a causal protective role of BDNF in the pathogenesis of CVD.
AU  - Kaess, B.M.*
AU  - Preis, S.R.*
AU  - Lieb, W.*
AU  - Beiser, A.S.*
AU  - Yang, Q.*
AU  - Chen, T.C.*
AU  - Hengstenberg, C.*
AU  - Erdmann, J.*
AU  - Schunkert, H.*
AU  - Seshadri, S*
AU  - Vasan, R.S.*
AU  - CARDIoGRAM Consortium (Döring, A.
AU  - Meisinger, C.
AU  - Meitinger, T.
AU  - Peters, A.
AU  - Wichmann, H.-E.)
C1  - 44397
C2  - 36912
CY  - Hoboken
TI  - Circulating brain-derived neurotrophic factor concentrations and the risk of cardiovascular disease in the community.
JO  - J. Am. Heart Assoc.
VL  - 4
IS  - 3
PB  - Wiley-blackwell
PY  - 2015
ER  - 

TY  - JOUR
AB  - BACKGROUND: Ubiquitous deletion of thioredoxin reductase 2 (Txnrd2) in mice is embryonically lethal and associated with abnormal heart development, while constitutive, heart-specific Txnrd2 inactivation leads to dilated cardiomyopathy and perinatal death. The significance of Txnrd2 in aging cardiomyocytes, however, has not yet been examined. METHODS AND RESULTS: The tamoxifen-inducible heart-specific αMHC-MerCreMer transgene was used to inactivate loxP-flanked Txnrd2 alleles in adult mice. Hearts and isolated mitochondria from aged knockout mice were morphologically and functionally analyzed. Echocardiography revealed a significant increase in left ventricular end-systolic diameters in knockouts. Fractional shortening and ejection fraction were decreased compared with controls. Ultrastructural analysis of cardiomyocytes of aged mice showed mitochondrial degeneration and accumulation of autophagic bodies. A dysregulated autophagic activity was supported by higher levels of lysosome-associated membrane protein 1 (LAMP1), microtubule-associated protein 1A/1B-light chain 3-I (LC3-I), and p62 in knockout hearts. Isolated Txnrd2-deficient mitochondria used less oxygen and tended to produce more reactive oxygen species. Chronic hypoxia inducible factor 1, α subunit stabilization and altered transcriptional and metabolic signatures indicated that energy metabolism is deregulated. CONCLUSIONS: These results imply a novel role of Txnrd2 in sustaining heart function during aging and suggest that Txnrd2 may be a modifier of heart failure.
AU  - Kiermayer, C.
AU  - Northrup, E.
AU  - Schrewe, A.
AU  - Walch, A.K.
AU  - Hrabě de Angelis, M.
AU  - Schoensiegel, F.*
AU  - Zischka, H.
AU  - Prehn, C.
AU  - Adamski, J.
AU  - Bekeredjian, R.*
AU  - Ivandic, B.*
AU  - Kupatt, C.*
AU  - Brielmeier, M.
C1  - 46409
C2  - 37514
TI  - Heart-specific knockout of the mitochondrial Thioredoxin reductase (Txnrd2) induces metabolic and contractile dysfunction in the aging myocardium.
JO  - J. Am. Heart Assoc.
VL  - 4
IS  - 7
PY  - 2015
ER  - 

TY  - JOUR
AB  - BACKGROUND: Calmodulin (CaM) mutations have been identified recently in subjects with congenital long QT syndrome (LQTS) or catecholaminergic polymorphic ventricular tachycardia (CPVT), but the mechanisms responsible for these divergent arrhythmia-susceptibility syndromes in this context are unknown. We tested the hypothesis that LQTS-associated CaM mutants disrupt Ca(2+) homeostasis in developing cardiomyocytes possibly by affecting either late Na current or Ca(2+)-dependent inactivation of L-type Ca(2+) current. METHODS AND RESULTS: We coexpressed CaM mutants with the human cardiac Na channel (NaV1.5) in tsA201 cells, and we used mammalian fetal ventricular cardiomyocytes to investigate LQTS- and CPVT-associated CaM mutations (LQTS- and CPVT-CaM). LQTS-CaM mutants do not consistently affect L-type Na current in heterologous cells or native cardiomyocytes, suggesting that the Na channel does not contribute to LQTS pathogenesis in the context of CaM mutations. LQTS-CaM mutants (D96V, D130G, F142L) impaired Ca(2+)-dependent inactivation, whereas the CPVT-CaM mutant N54I had no effect on Ca(2+)-dependent inactivation. LQTS-CaM mutants led to loss of Ca(2+)-transient entrainment with the rank order from greatest to least effect: CaM-D130G~CaM-D96V>CaM-F142L. This rank order follows measured Ca(2+)-CaM affinities for wild-type and mutant CaM. Acute isoproterenol restored entrainment for CaM-130G and CaM-D96V but caused irreversible cytosolic Ca(2+) overload for cells expressing a CPVT-CaM mutant. CONCLUSIONS: CaM mutations associated with LQTS may not affect L-type Na(+) current but may evoke defective Ca(2+)-dependent inactivation of L-type Ca(2+) current.
AU  - Yin, G.*
AU  - Hassan, F.*
AU  - Haroun, A.R.*
AU  - Murphy, L.L.*
AU  - Crotti, L.
AU  - Schwartz, P.J.*
AU  - George, A.L. Jr.*
AU  - Satin, J.*
C1  - 31670
C2  - 34718
TI  - Arrhythmogenic calmodulin mutations disrupt intracellular cardiomyocyte Ca2+ regulation by distinct mechanisms.
JO  - J. Am. Heart Assoc.
VL  - 3
IS  - 3
PY  - 2014
ER  - 

TY  - JOUR
AB  - BACKGROUND: Surgical treatment of peripheral artery disease, even if successful, does not prevent reoccurrence. Under these conditions, increased oxidative stress is a crucial determinant of tissue damage. Given its reported antioxidant effects, we investigated the potential of unacylated-ghrelin (UnAG) to reduce ischemia-induced tissue damage in a mouse model of peripheral artery disease. METHODS AND RESULTS: We show that UnAG but not acylated ghrelin (AG) induces skeletal muscle regeneration in response to ischemia via canonical p38/mitogen-actived protein kinase signaling UnAG protected against reactive oxygen species-induced cell injuries by inducing the expression of superoxide dismutase-2 (SOD-2) in satellite cells. This led to a reduced number of infiltrating CD68(+) cells and was followed by induction of the myogenic process and a reduction in functional impairment. Moreover, we found that miR-221/222, previously linked to muscle regeneration processes, was up-regulated and negatively correlated with p57(Kip2) expression in UnAG-treated mice. UnAG, unlike AG, promoted cell-cycle entry in satellite cells of mice lacking the genes for ghrelin and its receptor (GHSR1a). UnAG-induced p38/mitogen-actived protein kinase phosphorylation, leading to activation of the myogenic process, was prevented in SOD-2-depleted SCs. By siRNA technology, we also demonstrated that SOD-2 is the antioxidant enzyme involved in the control of miR-221/222-driven posttranscriptional p57(Kip2) regulation. Loss-of-function experiments targeting miR-221/222 and local pre-miR-221/222 injection in vivo confirmed a role for miR-221/222 in driving skeletal muscle regeneration after ischemia. CONCLUSIONS: These results indicate that UnAG-induced skeletal muscle regeneration after ischemia depends on SOD-2-induced miR-221/222 expression and highlight its clinical potential for the treatment of reactive oxygen species-mediated skeletal muscle damage.  
AU  - Togliatto, G.*
AU  - Trombetta, A.*
AU  - Dentelli, P.*
AU  - Cotogni, P.*
AU  - Rosso, A.*
AU  - Tschöp, M.H.
AU  - Granata, R.*
AU  - Ghigo, E.*
AU  - Brizzi, M.F.*
C1  - 28610
C2  - 33482
TI  - Unacylated ghrelin promotes skeletal muscle regeneration following hindlimb ischemia via SOD-2-mediated miR-221/222 expression.
JO  - J. Am. Heart Assoc.
VL  - 2
IS  - 6
PB  - Amer. Heart Assoc.
PY  - 2013
ER  -