Cardiac fibrosis is a detrimental factor that results in abnormalities in cardiac conduction, stiffening of the ventricular walls, and loss of contractility, thereby contributing to a variety of heart diseases, including hypertrophy, heart failure, and arrhythmia. A variety of stimuli such as infarction, pressure-overload, and oxidative stress can induce fibroblast differentiation and initiate fibrogenesis cascade. A better understanding of the mechanisms of cardiac fibrogenesis will provide novel insight into therapeutic approaches for treatment of fibrosis associated arrhythmia, hypertrophy and heart failure. The goal of this research program is to understand Ca2+ signaling mechanisms in cardiac fibroblasts (CFs) and how Ca2+ signals contribute to cardiac fibrogenesis as well as fibrosis associated heart diseases. In the first funding period, we have made substantial progress in revealing Ca2+ signaling mechanisms in cardiac fibrogenesis. First, we found that TRPM7 is the key Ca2+-permeable channel which is responsible for Ca2+ entry in cardiac fibroblasts. The finding that TRPM7 underlies the molecular mechanism of the major Ca2+- permeable channel in CFs is fundamental because it opens a new avenue for us to explore the potential roles of Ca2+ signals in cardiac fibrogenesis. Second, we found that TRPM7-mediated Ca2+ is required for TGF?1 induced fibroblast proliferation, differentiation, and collagen production. Since TGF-?1 is the predominant mediator for fibrogenesis, the involvement of TRPM7 in TGF-?1 signaling pathway suggests that TRPM7 plays an essential role in cardiac fibrogenesis, and may serve as a therapeutic target. Indeed, we found that TRPM7 mediated Ca2+ signal contributes significantly to fibrogenesis as demonstrated by many lines of evidence, including that TRPM7 is markedly up-regulated in AF patients and that knocking down TRPM7 impairs TGF-?1 mediated fibroblasts differentiation and collagen production. These novel findings allow us to ask more profound questions: First, how does Ca2+ signal contribute to fibrogenesis? Second, whether TRPM7 is a potential target for fibrosis related heart diseases. We have designed three specific aims to address these questions in the current application: 1) Investigate if genetically deletion of Trpm7 attenuates fibrosis and improves heart function;2) Determine the signaling pathways by which TRPM7-mediated Ca2+ signals are involved in cardiac fibrogenesis;3) Investigate whether TRPM7 influences fibrogenesis by enhancing TGF?1 production. We will apply multidisciplinary approaches including molecular biology, biochemistry, patch-clamp, Ca2+ imaging, transgenic and knockout to explore these question at the molecular, cellular, signaling, and in vivo animal model levels. The results of this study will not only reveal how Ca2+ signaling controls cardiac fibrogenesis, but also provide clinical insight into therapeutic approaches for fibrotic heart diseases.
Cardiac fibrosis is a detrimental factor which causes a variety of heart diseases including hypertrophy, heart failure and arrhythmia. Here we propose to investigate Ca2+ signaling mechanisms in mouse and human fibroblasts and to study how the Ca2+ permeable channel TRPM7 contribute to fibrosis related heart diseases. The results of this project will not only provide novel information about fundamental question regarding how Ca2+ signaling is involved in fibrogenesis, but also may provide a novel therapeutic target for fibrosis related heart diseases.
|Yue, Zhichao; Xie, Jia; Yu, Albert S et al. (2015) Role of TRP channels in the cardiovascular system. Am J Physiol Heart Circ Physiol 308:H157-82|
|Cagavi, Esra; Bartulos, Oscar; Suh, Carol Y et al. (2014) Functional cardiomyocytes derived from Isl1 cardiac progenitors via Bmp4 stimulation. PLoS One 9:e110752|
|Qin, Xin; Yue, Zhichao; Sun, Baonan et al. (2013) Sphingosine and FTY720 are potent inhibitors of the transient receptor potential melastatin 7 (TRPM7) channels. Br J Pharmacol 168:1294-312|
|Yue, Zhichao; Zhang, Yanhui; Xie, Jia et al. (2013) Transient receptor potential (TRP) channels and cardiac fibrosis. Curr Top Med Chem 13:270-82|
|Xie, Jia; Sun, Baonan; Du, Jianyang et al. (2011) Phosphatidylinositol 4,5-bisphosphate (PIP(2)) controls magnesium gatekeeper TRPM6 activity. Sci Rep 1:146|
|Yue, Lixia; Xie, Jia; Nattel, Stanley (2011) Molecular determinants of cardiac fibroblast electrical function and therapeutic implications for atrial fibrillation. Cardiovasc Res 89:744-53|
|Estes 3rd, N A Mark; Sacco, Ralph L; Al-Khatib, Sana M et al. (2011) American Heart Association atrial fibrillation research summit: a conference report from the American Heart Association. Circulation 124:363-72|
|Du, Jianyang; Xie, Jia; Zhang, Zheng et al. (2010) TRPM7-mediated Ca2+ signals confer fibrogenesis in human atrial fibrillation. Circ Res 106:992-1003|
|Chen, Hsiang-Chin; Xie, Jia; Zhang, Zheng et al. (2010) Blockade of TRPM7 channel activity and cell death by inhibitors of 5-lipoxygenase. PLoS One 5:e11161|
|Su, Li-Ting; Chen, Hsiang-Chin; Gonzalez-Pagan, Omayra et al. (2010) TRPM7 activates m-calpain by stress-dependent stimulation of p38 MAPK and c-Jun N-terminal kinase. J Mol Biol 396:858-69|
Showing the most recent 10 out of 16 publications