Browsing by Author "Wollert, Kai C."

Now showing 1 - 5 of 5
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    Cardiac Troponin I-interacting Kinase impacts cardiomyocyte S-phase activity but not cardiomyocyte proliferation
    (American Heart Association, 2023) Reuter, Sean P.; Soonpaa, Mark H.; Field, Dorothy; Simpson, Ed; Rubart-von der Lohe, Michael; Lee, Han Kyu; Sridhar, Arthi; Ware, Stephanie M.; Green, Nick; Li, Xiaochun; Ofner, Susan; Marchuk, Douglas A.; Wollert, Kai C.; Field, Loren J.; Pediatrics, School of Medicine
    Background: Identifying genetic variants that affect the level of cell cycle reentry and establishing the degree of cell cycle progression in those variants could help guide development of therapeutic interventions aimed at effecting cardiac regeneration. We observed that C57Bl6/NCR (B6N) mice have a marked increase in cardiomyocyte S-phase activity after permanent coronary artery ligation compared with infarcted DBA/2J (D2J) mice. Methods: Cardiomyocyte cell cycle activity after infarction was monitored in D2J, (D2J×B6N)-F1, and (D2J×B6N)-F1×D2J backcross mice by means of bromodeoxyuridine or 5-ethynyl-2'-deoxyuridine incorporation using a nuclear-localized transgenic reporter to identify cardiomyocyte nuclei. Genome-wide quantitative trait locus analysis, fine scale genetic mapping, whole exome sequencing, and RNA sequencing analyses of the backcross mice were performed to identify the gene responsible for the elevated cardiomyocyte S-phase phenotype. Results: (D2J×B6N)-F1 mice exhibited a 14-fold increase in cardiomyocyte S-phase activity in ventricular regions remote from infarct scar compared with D2J mice (0.798±0.09% versus 0.056±0.004%; P<0.001). Quantitative trait locus analysis of (D2J×B6N)-F1×D2J backcross mice revealed that the gene responsible for differential S-phase activity was located on the distal arm of chromosome 3 (logarithm of the odds score=6.38; P<0.001). Additional genetic and molecular analyses identified 3 potential candidates. Of these, Tnni3k (troponin I-interacting kinase) is expressed in B6N hearts but not in D2J hearts. Transgenic expression of TNNI3K in a D2J genetic background results in elevated cardiomyocyte S-phase activity after injury. Cardiomyocyte S-phase activity in both Tnni3k-expressing and Tnni3k-nonexpressing mice results in the formation of polyploid nuclei. Conclusions: These data indicate that Tnni3k expression increases the level of cardiomyocyte S-phase activity after injury.
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    Cardioprotection vs. regeneration: the case of extracellular vesicle-derived microRNAs
    (Springer, 2021-03-19) Wollert, Kai C.; Field, Loren J.; Pediatrics, School of Medicine
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    Fibroblast GATA-4 and GATA-6 promote myocardial adaptation to pressure overload by enhancing cardiac angiogenesis
    (Springer, 2021-04-19) Dittrich, Gesine M.; Froese, Natali; Wang, Xue; Kroeger, Hannah; Wang, Honghui; Szaroszyk, Malgorzata; Malek‑Mohammadi, Mona; Cordero, Julio; Keles, Merve; Korf‑Klingebiel, Mortimer; Wollert, Kai C.; Geffers, Robert; Mayr, Manuel; Conway, Simon J.; Dobreva, Gergana; Bauersachs, Johann; Heineke, Joerg; Pediatrics, School of Medicine
    Heart failure due to high blood pressure or ischemic injury remains a major problem for millions of patients worldwide. Despite enormous advances in deciphering the molecular mechanisms underlying heart failure progression, the cell-type specific adaptations and especially intercellular signaling remain poorly understood. Cardiac fibroblasts express high levels of cardiogenic transcription factors such as GATA-4 and GATA-6, but their role in fibroblasts during stress is not known. Here, we show that fibroblast GATA-4 and GATA-6 promote adaptive remodeling in pressure overload induced cardiac hypertrophy. Using a mouse model with specific single or double deletion of Gata4 and Gata6 in stress activated fibroblasts, we found a reduced myocardial capillarization in mice with Gata4/6 double deletion following pressure overload, while single deletion of Gata4 or Gata6 had no effect. Importantly, we confirmed the reduced angiogenic response using an in vitro co-culture system with Gata4/6 deleted cardiac fibroblasts and endothelial cells. A comprehensive RNA-sequencing analysis revealed an upregulation of anti-angiogenic genes upon Gata4/6 deletion in fibroblasts, and siRNA mediated downregulation of these genes restored endothelial cell growth. In conclusion, we identified a novel role for the cardiogenic transcription factors GATA-4 and GATA-6 in heart fibroblasts, where both proteins act in concert to promote myocardial capillarization and heart function by directing intercellular crosstalk.
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    Inactivation of Sox9 in fibroblasts reduces cardiac fibrosis and inflammation
    (American Society for Clinical Investigation, 2019-07-16) Scharf, Gesine M.; Kilian, Katja; Cordero, Julio; Wang, Yong; Grund, Andrea; Hofmann, Melanie; Froese, Natali; Wang, Xue; Kispert, Andreas; Kist, Ralf; Conway, Simon J.; Geffers, Robert; Wollert, Kai C.; Dobreva, Gergana; Bauersachs, Johann; Heineke, Joerg; Pediatrics, School of Medicine
    Fibrotic scarring drives the progression of heart failure after myocardial infarction (MI). Therefore, the development of specific treatment regimens to counteract fibrosis is of high clinical relevance. The transcription factor SOX9 functions as an important regulator during embryogenesis, but recent data point towards an additional causal role in organ fibrosis. We show here that SOX9 is upregulated in the scar after MI in mice. Fibroblast specific deletion of Sox9 ameliorated MI-induced left ventricular dysfunction, dilatation and myocardial scarring in vivo. Unexpectedly, deletion of Sox9 also potently eliminated persisting leukocyte infiltration of the scar in the chronic phase after MI. RNA-sequencing from the infarct scar revealed that Sox9 deletion in fibroblasts resulted in strongly downregulated expression of genes related to extracellular matrix, proteolysis and inflammation. Importantly, Sox9 deletion in isolated cardiac fibroblasts in vitro similarly affected gene expression as in the cardiac scar and reduced fibroblast proliferation, migration and contraction capacity. Together, our data demonstrate that fibroblast SOX9 functions as a master regulator of cardiac fibrosis and inflammation and might constitute a novel therapeutic target during MI.
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    Meteorin-like promotes heart repair through endothelial KIT receptor tyrosine kinase
    (American Association for the Advancement of Science, 2022) Reboll, Marc R.; Klede, Stefanie; Taft, Manuel H.; Cai, Chen-Leng; Field, Loren J.; Lavine, Kory J.; Koenig, Andrew L.; Fleischauer, Jenni; Meyer, Johann; Schambach, Axel; Niessen, Hans W.; Kosanke, Maike; van den Heuvel, Joop; Pich, Andreas; Bauersachs, Johann; Wu, Xuekun; Zheng, Linqun; Wang, Yong; Korf-Klingebiel, Mortimer; Polten, Felix; Wollert, Kai C.; Pediatrics, School of Medicine
    Effective tissue repair after myocardial infarction entails a vigorous angiogenic response, guided by incompletely defined immune cell-endothelial cell interactions. We identify the monocyte- and macrophage-derived cytokine METRNL (meteorin-like) as a driver of postinfarction angiogenesis and high-affinity ligand for the stem cell factor receptor KIT (KIT receptor tyrosine kinase). METRNL mediated angiogenic effects in cultured human endothelial cells through KIT-dependent signaling pathways. In a mouse model of myocardial infarction, METRNL promoted infarct repair by selectively expanding the KIT-expressing endothelial cell population in the infarct border zone. Metrnl-deficient mice failed to mount this KIT-dependent angiogenic response and developed severe postinfarction heart failure. Our data establish METRNL as a KIT receptor ligand in the context of ischemic tissue repair.