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Cardiac Cellular Remodeling from the Outside in

其他書名	Extracellular Matrix Proteins and MRNA Modifications Dictate Cardiomyocyte Hypertrophy
出版	Ohio State University, 2021
URL	http://books.google.com.hk/books?id=hlb8zwEACAAJ&hl=&source=gbs_api

註釋Heart disease is a leading cause of morbidity and mortality in the United States. Cardiac remodeling is a universal facet of heart disease, and occurs in predictable patterns in response to stress stimuli. Although stress-induced remodeling is a multifaceted and complex process, two major components of remodeling include cardiomyocyte hypertrophy and myocardial fibrosis. Although many cell types within the heart contribute to cardiac remodeling, cardiomyocytes are often considered the effectors of cardiac hypertrophy, which over time leads to decreased cardiac function and symptomatic heart failure. Although the physical and genetic changes associated with cardiomyocyte hypertrophy itself are predictable and well documented, the precise mechanisms by which certain stimuli may cause these changes are exceedingly complex. In this dissertation I demonstrate how two separate processes, extracellular matrix-resident protein interactions and the small chemical mRNA modification m6A, can induce cardiomyocyte remodeling and may be manipulated to understand how a cardiomyocyte responds to external stressors. First, I examine the role of connective tissue growth factor (CTGF or CCN2) in the pathogenesis of stress-induced myocardial fibrotic remodeling. By using cell-specific genetic knockdown of CCN2 in mouse models, I determined that cardiomyocyte-derived CCN2 is dispensable for angiotensin II- or TGFb1- induced fibrosis; in contrast, fibroblast-derived CCN2 is essential for myofibroblast transdifferentiation and fibrotic remodeling in vivo. I next investigate the contribution of microfibrillar-associated protein 4 (MFAP4) in the pathogenesis of cardiomyocyte hypertrophy. MFAP4 is a TGFb1-inducible extracellular matrix protein that is upregulated in the heart in response to cardiac stress and is highly expressed by nonmyocytes but not cardiomyocytes. Using an MFAP4 knockout mouse model, I determine that the loss of MFAP4 leads to exacerbated cardiomyocyte hypertrophy and decreased cardiac function in response to either chronic pressure overload or acute neurohumoral stimulation. Furthermore, MFAP4 knockout leads to dysregulated hypertrophic signaling in vivo, including inappropriately overactivated maladaptive ERK1/2 signaling and decreased protective integrin-mediated FAK and Akt activation. MFAP4 supplementation in isolated cardiomyocytes prevents phenylephrine-induced cell growth and normalizes the balance between GPCR and integrin-based signaling cascades. Finally, I explore the role of the common mRNA modification m6A and its writer enzyme METTL3 in the maintenance of cardiac homeostasis and cardiac remodeling following stress. m6A-modified mRNA levels are increased in hypertrophic cardiomyocytes, and overexpression of m6A writer METTL3 in mice leads to spontaneous hypertrophy and resistance to chronic pressure-overload induced cardiac stress. In contrast, murine METTL3 knockdown leads to spontaneous cardiac dilation and functional decline by 8 months of age, as well as an inability to undergo compensatory hypertrophy with stress. Mechanistically, METTL3 and increased m6A deposition stabilizes mRNAs associated with the MAP kinase pathway, well documented in the pathogenesis of cardiac hypertrophy. The increasing burden of heart disease in the United States necessitates novel therapeutic approaches to ameliorate cardiac remodeling and improve patient outcomes. The results of these studies indicate that the extracellular matrix factors CTGF/CCN2 and MFAP4, as well as the m6A methyltransferase METTL3, may be potential therapeutic targets for cardiac remodeling, and the knowledge herein will benefit future research accordingly.