Heart failure after myocardial infarction (MI) is a significant cause of morbidity and mortality. Though pharmacological advances have significantly reduced mortality, the residual risk of post MI-induced heart failure is increasing. This necessitates development of new approaches to preserve heart function. The extent of tissue damage in the acute phase of MI is a critical determinant of the degree of subsequent adverse remodeling that leads to impaired cardiac performance. As such, an important goal is to minimize infarct size, which is a function of cardiomyocyte (CM) death. Efficient phagocytic removal of dying CMs by efferocytosis is critical to initiating resolving inflammation and promoting heart repair. Importantly, reduced phagocytic clearance of dying CMs is directly correlated with increased morbidity and mortality post MI. Recent studies have shown monocyte subsets to be differentially responsible for phagocytic and repair functions in the heart. Beyond the cellular level, the molecular pathways within myocardial phagocytes, required for efferocytosis- directed inflammation resolution in the heart, remain unknown. My laboratory has made the discovery that inactivation of efferocytosis signaling pathways worsen heart repair after MI, paving the way for new a new class of molecular targets to promote wound healing in the heart. Our studies show that suppression of CM """"""""don't eat me"""""""" ligands enhance engulfment by phagocytes, and that the apoptotic cell receptor MERTK, is required for CM efferocytosis. Our data in non-gene targeted mice and humans indicate MERTK is naturally inactivated during MI by proteolysis and hypoxia inducible factors (HIFs) and importantly, murine MERTK deficiency increases adverse myocardial ventricular remodeling and promotes heart failure after MI. These data implicate apoptotic cell receptors and CM don't-eat-me ligands as candidates for defective efferocytosis post MI. These initial results led to several new lines of investigation, which are the focus of this proposal, including (I) the degree to which MERTK-dependent efferocytosis and proteolysis drives the extent of post MI repair in the setting of risk factors suh as hyperlipidemia and clinically-relevant reperfusion, (II) MERTK- dependent and independent mechanisms of efferocytosis and inflammation resolution during hypoxia, and (III) novel CM interactions with M?s.
Efferocytosis is the phagocytic clearance of dying cells. Inefficient efferocytosis, such as after death of heart cells during a heart attack, permits increased cell death and loss of contractile heart function that leads to heart failure. The studie outlined herein are the first to test the clinical relevance and mechanistic basis of enhancing efferocytosis after heart attack.
|Glinton, Kristofor; DeBerge, Matthew; Yeap, Xin-Yi et al. (2018) Acute and chronic phagocyte determinants of cardiac allograft vasculopathy. Semin Immunopathol 40:593-603|
|Yang, Yi; Kong, Sinyi; Zhang, Yana et al. (2018) The endoplasmic reticulum-resident E3 ubiquitin ligase Hrd1 controls a critical checkpoint in B cell development in mice. J Biol Chem 293:12934-12944|
|Dehn, Shirley; Thorp, Edward B (2018) Myeloid receptor CD36 is required for early phagocytosis of myocardial infarcts and induction of Nr4a1-dependent mechanisms of cardiac repair. FASEB J 32:254-264|
|Jia, Yuzhi; Liu, Ning; Viswakarma, Navin et al. (2018) PIMT/NCOA6IP Deletion in the Mouse Heart Causes Delayed Cardiomyopathy Attributable to Perturbation in Energy Metabolism. Int J Mol Sci 19:|
|Viaud, Manon; Ivanov, Stoyan; Vujic, Nemanja et al. (2018) Lysosomal Cholesterol Hydrolysis Couples Efferocytosis to Anti-Inflammatory Oxysterol Production. Circ Res 122:1369-1384|
|Cai, Bishuang; Thorp, Edward B; Doran, Amanda C et al. (2017) MerTK receptor cleavage promotes plaque necrosis and defective resolution in atherosclerosis. J Clin Invest 127:564-568|
|Rowley, Anne H; Baker, Susan C; Kim, Kwang-Youn A et al. (2017) Allograft Inflammatory Factor-1 Links T-Cell Activation, Interferon Response, and Macrophage Activation in Chronic Kawasaki Disease Arteritis. J Pediatric Infect Dis Soc 6:e94-e102|
|Kang, Hee Kap; Wang, Shusen; Dangi, Anil et al. (2017) Differential Role of B Cells and IL-17 Versus IFN-? During Early and Late Rejection of Pig Islet Xenografts in Mice. Transplantation 101:1801-1810|
|DeBerge, Matthew; Yeap, Xin Yi; Dehn, Shirley et al. (2017) MerTK Cleavage on Resident Cardiac Macrophages Compromises Repair After Myocardial Ischemia Reperfusion Injury. Circ Res 121:930-940|
|Zhang, Shuang; Yeap, Xin-Yi; DeBerge, Matthew et al. (2017) Acute CD47 Blockade During Ischemic Myocardial Reperfusion Enhances Phagocytosis-Associated Cardiac Repair. JACC Basic Transl Sci 2:386-397|
Showing the most recent 10 out of 31 publications