Heart disease is a leading case of mortality and mortality in the United States and is rapidly emerging as a major public health problem in the developing world. The adult heart possesses a limited ability to regenerate and is unable to replace damaged heart muscle after cardiac injury with new cardiac muscle cells. Consequently, fibrosis and scarring are the typical "response to injury" seen in the adult heart. Nonfunctioning scar tissue does not contribute towards the pumping ability of the heart and over time the increased hemodynamic burden imposed on the heart by the fibrous tissue leads to adverse cardiac remodeling, cardiac dilatation and heart failure. Consequently strategies to inhibit cardiac fibrosis after myocardial infarction hold great promise for preserving cardiac function after myocardial infarction. We demonstrate in this proposal that, intra-cardiac injection of Secreted related frizzled protein 2 (Sfrp2), an extracellular Wnt antagonist, 48 hours after myocardial injury, dramatically decreases cardiac scarring. Although this suggests a role of Wnts as pro- fibrotic molecules, the expression and function of Wnts in the infarcted heart are completely unknown. Wnts are a family of 19 lipophilic proteins that play a crucial role during organogenesis including heart development but the adult uninjured heart minimally expresses Wnts. We provide evidence that several Wnts are re- expressed following injury and expression of Wnt1 is dramatically elevated following cardiac injury and induces cardiac fibroblast proliferation and activation. Cardiac fibroblasts at the infarct site are Wnt responsive and up-regulate downstream mediators of Wnt1 signaling. We further demonstrate that the embryonic heart at sites of fibroblast generation is also Wnt responsive. Considering these observations, we have hypothesized (i) that the adult heart recapitulates a Wnt1 dependent developmental program after cardiac injury to promote cardiac fibrosis and repair and (ii) interruption of Wnt signaling in the cardiac fibroblast will decrease cardiac fibrosis and preserve cardiac function after injury.
Our specific aims are to A) To determine whether the injured heart recapitulates a developmental program of Wnt1 expression and response B) To determine downstream targets of Wnt1 that mediate cardiac fibroblast activation and finally C) To determine changes in cardiac function following fibroblast specific interruption of Wnt/2 catenin signaling in the infarcted heart. In summary, our proposed studies using molecular, genetic and physiologic approaches will dissect the role and mechanisms of Wnt1 in regulating cardiac fibrosis in the injured heart. Identification of cell components secreting Wnts, target cells responding to Wnts, and physiological benefits of interrupting Wnt1 signaling in the infarcted heart can potentially lead to novel therapies for myocardial infarction.
PROJECT NARRATIVE The adult heart following a heart attack does not regenerate damaged muscle but forms a non-functioning scar in the injured region. We have identified that a developmentally important molecule known as Wnt1 contributes to scar formation in the injured heart. In this proposal, we will determine how Wnt1 regulates scar formation in the injured heart and aim to minimize scar formation and improve cardiac function through manipulation of Wnt signaling.
|Murray, Iain R; Baily, James E; Chen, William C W et al. (2016) Skeletal and cardiac muscle pericytes: Functions and therapeutic potential. Pharmacol Ther :|
|Deb, Arjun; Wang, Yibin (2015) Hypertrophic preconditioning: short-term tricks for long-term gain. Circulation 131:1468-70|
|Deb, Arjun (2014) Cell-cell interaction in the heart via Wnt/Î²-catenin pathway after cardiac injury. Cardiovasc Res 102:214-23|
|Ubil, Eric; Duan, Jinzhu; Pillai, Indulekha C L et al. (2014) Mesenchymal-endothelial transition contributes to cardiac neovascularization. Nature 514:585-90|
|Deb, Arjun; Ubil, Eric (2014) Cardiac fibroblast in development and wound healing. J Mol Cell Cardiol 70:47-55|
|Duan, JinZhu; Lee, Yueh; Jania, Corey et al. (2013) Rib fractures and death from deletion of osteoblast Î²catenin in adult mice is rescued by corticosteroids. PLoS One 8:e55757|
|Duan, Jinzhu; Gherghe, Costin; Liu, Dianxin et al. (2012) Wnt1/Î²catenin injury response activates the epicardium and cardiac fibroblasts to promote cardiac repair. EMBO J 31:429-42|
|Gherghe, Costin M; Duan, Jinzhu; Gong, Jucheng et al. (2011) Wnt1 is a proangiogenic molecule, enhances human endothelial progenitor function, and increases blood flow to ischemic limbs in a HGF-dependent manner. FASEB J 25:1836-43|
|Deb, Arjun; Patterson, Cam (2010) Closer to fine: fewer steps to endothelial stemness. Arterioscler Thromb Vasc Biol 30:1880-1|
|Huang, Jing; Zhang, Zhiping; Guo, Jian et al. (2010) Genetic modification of mesenchymal stem cells overexpressing CCR1 increases cell viability, migration, engraftment, and capillary density in the injured myocardium. Circ Res 106:1753-62|
Showing the most recent 10 out of 11 publications