Electronic Thesis and Dissertation Repository


Doctor of Philosophy


Physiology and Pharmacology


Dr. Qingping Feng


Complete occlusion of a coronary artery causes myocardial infarction (MI), resulting in cardiomyocyte cell death. The surviving myocardium undergoes a deleterious remodeling process which causes further injury, and can ultimately result in heart failure. Despite therapeutic advances that have prolonged life, MI remains a leading cause of death worldwide and imparts a significant economic burden. The advancement of treatments to improve cardiac repair post-MI requires the discovery of new targeted treatment strategies. Epicardial-to-mesenchymal transition (EMT) occurs post-MI as a mechanism to support neovascularization and cardiac healing. However, the endogenous EMT is not enough to support sufficient repair. The transcription factor Wilms’ tumor 1 (Wt1) and the primary cilium regulate EMT. Furthermore, the long non-coding RNA (lncRNA) Malat1 is not only known to regulate EMT, but also mitigates cell death from injury. Little is known about the roles of Wt1, primary cilia, and Malat1 in relation to neonatal cardiac regeneration and adult cardiac repair post-MI. The aim of thesis was to investigate cardiac repair mechanisms related to EMT, primary cilia, and Malat1. To study the effects of deficiency of Wt1 and Malat1, a reproducible model of cardiac regeneration using coronary artery ligation to induce MI was developed in neonatal mice. We demonstrated the robust capacity for neonatal cardiac regeneration as neither Wt1 nor Malat1 deficiency affected the regenerative response. In the adult mouse, MI was induced to investigate the role of the primary cilium in EMT and repair post-MI, and the effects of Malat1 deficiency on acute MI pathology. We found that indeed epicardial cells are ciliated, and primary ciliary disassembly supports EMT post-MI, which enhances the contribution of epicardium-derived cells (EPDCs) to neovascularization. This reduced deleterious cardiac remodeling and preserved cardiac function. Contrastingly, Malat1 deficiency augmented cardiac cell death from MI. Unexpectedly, rather than affecting apoptosis, Malat1 deficiency augmented necroptotic cell death post-MI. Overall, this thesis is the first to show that in the adult heart, the primary cilium regulates epicardial EMT and the lncRNA Malat1 governs the propensity for necroptosis from ischemic injury. Both the primary cilium and Malat1 may serve as targets in the development of therapeutics to treat MI in the future.