Date of Award

12-16-2020

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry

First Advisor

Ming-hui Zou

Second Advisor

Zhonglin Xie

Third Advisor

Christopher Basler

Fourth Advisor

Binghe Wang

Abstract

Macroautophagy (hereafter autophagy) is a fundamental cellular process that removes unnecessary or dysfunctional components. It allows the orderly degradation and recycling of cellular components. Mitophagy refers to the selective removal of damaged mitochondria via autophagy pathway. In addition to utilizing core autophagic machinery components, mitophagy exploits a variety of molecules, such as PTEN-induced putative kinase protein 1 (PINK1) and Parkin, to identify and eliminate damaged or superfluous mitochondria. Dysregulation of autophagy and mitophagy contributes to a variety of human disorders, including cardiovascular diseases, such as atherosclerosis and diabetic cardiomyopathy. Vascular smooth muscle cells (VSMCs) are a major component of the vascular media, and are vital for maintaining vessel homeostasis. Migration of VSMCs from the media to intima occurs during the development of atherosclerosis. Although alterations in autophagy activity have been reported in atherosclerosis, further investigation is required to delineate the mechanism by which autophagy regulates microtubule stability and cell migration. Diabetic cardiomyopathy, which develops in the absence of traditional risk factors, is a major cause of heart failure in Type 2 diabetic patients. Although multiple factors may collectively contribute to the development of diabetic cardiomyopathy, there is an urgent need to determine the role of autophagy in the development of diabetic cardiomyopathy.

This dissertation has explored the role of autophagy and mitophagy in regulating VSMCs migration as well as in the development of diabetic cardiomyopathy, using comprehensive physiological, pathophysiological, molecular, and genetic approaches. We show that activation of autophagy selectively degrades KAT2A/GCN5, a histone acetyltransferase that acetylates α-tubulin in VSMCs, leading to microtubule instability and promotion of VSMC migration. In diabetic heart, defective autophagy and PINK1/Parkin-mediated mitophagy are regulated by bromodomain-containing protein 4 (BRD4), a bromodomain and extra-terminal domain (BET) family of proteins. Administration of JQ1, one of the BET bromodomain inhibitors, restores PINK1/Parkin-mediated mitophagy and prevents high-fat-diet induced diabetic cardiomyopathy. Collectively, our work suggests that autophagy suppression in VSMCs is an important therapeutic target for atherosclerosis and that suppression of BRD4 may be a new therapeutic approach for diabetic cardiomyopathy.

DOI

https://doi.org/10.57709/20395014

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