TY  - JOUR
AB  - CRELD1 (Cysteine-Rich with EGF-Like Domains 1) is a risk gene for non-syndromic atrioventricular septal defects in human patients. In a mouse model, Creld1 has been shown to be essential for heart development, particularly in septum and valve formation. However, due to the embryonic lethality of global Creld1 knockout (KO) mice, its cell type-specific function during peri- and postnatal stages remains unknown. Here, we generated conditional Creld1 KO mice lacking Creld1 either in the endocardium (KOTie2) or the myocardium (KOMyHC). Using a combination of cardiac phenotyping, histology, immunohistochemistry, RNA-sequencing and flow cytometry, we demonstrate that Creld1 function in the endocardium is dispensable for heart development. Lack of myocardial Creld1 causes extracellular matrix remodeling and trabeculation defects by modulation of the Notch1 signaling pathway. Hence, KOMyHC mice die early postnatally due to myocardial hypoplasia. Our results reveal that Creld1 not only controls the formation of septa and valves at an early stage during heart development, but also cardiac maturation and function at a later stage. These findings underline the central role of Creld1 in mammalian heart development and function.
AU  - Beckert, V.*
AU  - Rassmann, S.*
AU  - Kayvanjoo, A.H.*
AU  - Klausen, C.*
AU  - Bonaguro, L.*
AU  - Botermann, D.S.*
AU  - Krause, M.*
AU  - Moreth, K.
AU  - Spielmann, N.
AU  - Da Silva-Buttkus, P.
AU  - Fuchs, H.
AU  - Gailus-Durner, V.
AU  - Hrabě de Angelis, M.
AU  - Händler, K.*
AU  - Ulas, T.*
AU  - Aschenbrenner, A.C.*
AU  - Mass, E.*
AU  - Wachten, D.*
C1  - 61676
C2  - 50385
CY  - The Boulevard, Langford Lane, Kidlington, Oxford Ox5 1gb, Oxon, England
SP  - 45-56
TI  - Creld1 regulates myocardial development and function.
JO  - J. Mol. Cell. Cardiol.
VL  - 156
PB  - Elsevier Sci Ltd
PY  - 2021
SN  - 0022-2828
ER  - 

TY  - JOUR
AB  - A key response of the myocardium to stress is the secretion of factors with paracrine or endocrine function. Intriguing in this respect is peptidase inhibitor 16 (PI16), a member of the CAP family of proteins which we found to be highly upregulated in cardiac disease. Up to this point, the mechanism of action and physiological function of PI16 remained elusive. Here, we show that PI16 is predominantly expressed by cardiac fibroblasts, which expose PI16 to the interstitium via a glycophosphatidylinositol-(GPI) membrane anchor. Based on a reported genetic association of PI16 and plasma levels of the chemokine chemerin, we investigated whether PI16 regulates post-translational processing of its precursor pro-chemerin. PI16-deficient mice were engineered and found to generate higher levels of processed chemerin than wildtype mice. Purified recombinant PI16 efficiently inhibited cathepsin K, a chemerin-activating protease, in vitro. Moreover, we show that conditioned medium from PI16-overexpressing cells impairs the activation of pro-chemerin. Together, our data indicate that PI16 suppresses chemerin activation in the myocardium and suggest that this circuit may be part of the cardiac stress response.
AU  - Regn, M.*
AU  - Laggerbauer, B.*
AU  - Jentzsch, C.*
AU  - Ramanujam, D.*
AU  - Ahles, A.*
AU  - Sichler, S.*
AU  - Calzada-Wack, J.
AU  - Koenen, R.*
AU  - Braun, A.*
AU  - Nieswandt, B.*
AU  - Engelhardt, S.*
C1  - 49287
C2  - 41727
CY  - Oxford
SP  - 57-64
TI  - Peptidase inhibitor 16 is a membrane-tethered regulator of chemerin processing in the myocardium.
JO  - J. Mol. Cell. Cardiol.
VL  - 99
PB  - Elsevier Sci Ltd
PY  - 2016
SN  - 0022-2828
ER  - 

TY  - JOUR
AB  - Deep sequencing techniques and advanced data analysis methods recently enabled the characterization of thousands of circular RNA isoforms (circRNAs) from a number of tissues and organisms. There is emerging evidence that some circRNAs may have important biological functions or serve as diagnostic biomarkers in disease conditions. In order to analyze circRNA expression in the heart and its changes in different conditions we performed RNA-Seq analysis of ribosome-depleted libraries from rats (neonatal and adult), mice (sham or after transverse aortic constriction, TAC) and humans (failing, non-failing). All samples were sequenced after a treatment with exonuclease RNase R or a mock treatment and >9000 candidate circRNAs were detected for each species. Additionally, we performed separate isolation of nuclear and cytoplasmic RNA and co-immunoprecipitated RNA interacting with endogenous argonaute 2 (Ago2) in primary cardiac myocytes. We found circRNAs to be significantly enriched in the cytoplasm compared to linear transcripts and to have a similar level of association with Ago2. Notably in all three species we observed dozens of circRNAs arising from the titin (Ttn) gene, which is known to undergo highly complex alternative splicing during heart maturation. Correspondingly we observed extensive differential regulation of Ttn circRNAs between neonatal and adult rat hearts, suggesting that circRNA formation could be involved in the regulation of titin splicing. We expect that our inventory of cardiac circRNAs, as well as the information on their conservation and differential expression will provide an important basis for further studies addressing their function and suitability as biomarkers.
AU  - Werfel, S.*
AU  - Nothjunge, S.*
AU  - Schwarzmayr, T.
AU  - Strom, T.M.
AU  - Meitinger, T.
AU  - Engelhardt, S.*
C1  - 49212
C2  - 40692
CY  - Oxford
SP  - 103-107
TI  - Characterization of circular RNAs in human, mouse and rat hearts.
JO  - J. Mol. Cell. Cardiol.
VL  - 98
PB  - Elsevier Sci Ltd
PY  - 2016
SN  - 0022-2828
ER  - 

TY  - JOUR
AB  - The inflammatory cytokine tumor necrosis factor alpha (TNFalpha) is controversially discussed in ischemia/reperfusion damage of the heart. Purpose of this study was to elucidate cellular sources of TNFalpha and parameters which possibly influence its release in the heart following ischemia. Isolated hearts of mice were subjected to 15 min of global ischemia and 90 min of reperfusion. We employed hearts of various mice knock-out strains (interleukin-6(-/-), matrix metalloprotease-7(-/-), mast-cell deficient WBB6F1-Kit(W)/Kit(W-v), TNF-R1(-/-)) and wildtype mice, the latter perfused without and with infusion of cycloheximide or TNFalpha-cleaving-enzyme inhibitor (TAPI-2). Normoxic control hearts showed basal release of TNFalpha during the whole experiment. Immunohistology identified cardiac mast cells, macrophages and endothelial cells as main sources. TNFalpha release was stimulated during postischemic reperfusion, occurring in a two-peak pattern: directly after ischemia (0-10 min) and again after 60-90 min. The first peak mainly reflects tissue washout of TNFalpha accumulated during ischemia. The second, protracted peak arose continuously from the basal level and was abolished by protein synthesis inhibitor cycloheximide. Both properties are characteristic for de novo synthesis of TNFalpha, e.g., in cardiac muscle cells. However, immunohistological staining for TNFalpha failed in cardiomyocytes after 90 min of reperfusion. In contrast to hearts of TNF-R1(-/-) and Kit(W/W-v)-mice, those of IL-6(-/-) and MMP-7(-/-) mice lacked the late TNFalpha peak. TAPI did not suppress release of TNFalpha. While autostimulation via TNF-R1 also does not seem obligatory and mast cell can be ignored as source of the second peak, IL-6 may support de novo synthesis of TNFalpha. Additionally, TNFalpha release may essentially involve cleavage of membrane bound TNFalpha by MMP-7.
AU  - Reil, J.-C.*
AU  - Gilles, S.*
AU  - Zahler, S.*
AU  - Brandl, A.*
AU  - Drexler, H.*
AU  - Hültner, L.
AU  - Matrisian, L.M.*
AU  - Welsch, U.*
AU  - Becker, B.F.*
C1  - 3912
C2  - 24209
SP  - 133-141
TI  - Insights from knock-out models concerning postischemic release of TNFalpha from isolated mouse hearts.
JO  - J. Mol. Cell. Cardiol.
VL  - 42
PB  - Elsevier
PY  - 2007
SN  - 0022-2828
ER  -