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Cardiovasc Res. 2019 Aug 22. pii: cvz216. doi: 10.1093/cvr/cvz216. [Epub ahead of print]

Overexpression of p53 due to excess protein O-GlcNAcylation is associated with coronary microvascular disease in type 2 diabetes.

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Department of Physiology, The University of Arizona, Tucson, Arizona.
Department of Cardiology, Xijing Hospital, Fourth Military University, Shaanxi, China.
Department of Medicine, University of California, San Diego, La Jolla, California.
State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
Department of Medicine, The University of Arizona, Tucson, Arizona.



We previously reported that increased protein O-GlcNAcylation in diabetic mice led to vascular rarefaction in the heart. In this study, we aimed to study whether and how coronary endothelial cell (EC) apoptosis is enhanced by protein O-GlcNAcylation and thus induces coronary microvascular disease (CMD) and subsequent cardiac dysfunction in diabetes. We hypothesize that excessive protein O-GlcNAcylation increases p53 that leads to CMD and reduced cardiac contractility.


We conducted in vivo functional experiments in control mice, TALLYHO/Jng (TH) mice, a polygenic type 2 diabetic (T2D) model, and EC-specific O-GlcNAcase (OGA, an enzyme that catalyzes the removal of O-GlcNAc from proteins)-overexpressing TH mice, as well as in vitro experiments in isolated ECs from these mice. TH mice exhibited a significant increase in coronary EC apoptosis and reduction of coronary flow velocity reserve (CFVR), an assessment of coronary microvascular function, in comparison to wild type mice. The decreased CFVR due at least partially to EC apoptosis was associated with decreased cardiac contractility in TH mice. Western blot experiments showed that p53 protein level was significantly higher in in coronary ECs from TH mice and T2D patients than in control ECs. High glucose treatment also increased p53 protein level in control ECs. Furthermore, overexpression of OGA decreased protein O-GlcNAcylation and downregulated p53 in coronary ECs, and conferred a protective effect on cardiac function in TH mice. Inhibition of p53 with pifithrin-α attenuated coronary EC apoptosis and restored CFVR and cardiac contractility in TH mice.


The data from this study indicate that inhibition of p53 or downregulation of p53 by OGA overexpression attenuates coronary EC apoptosis and improves CFVR and cardiac function in diabetes. Lowering coronary endothelial p53 levels via OGA overexpression could be a potential therapeutic approach for CMD in diabetes.


Coronary microvascular disease (CMD) is one of the causes of cardiac ischemia and heart attack in patients with diabetes; however, the molecular mechanisms which chronic hyperglycemia leads to CMD is not well understood. Our study demonstrated that lowering p53 (an apoptosis inducer) via overexpression of OGA (an enzyme to reduce protein O-GlcNAcylation) inhibited coronary endothelial apoptosis, increased coronary flow, and improved cardiac contractility in diabetes. Therefore, inhibiting p53 is a potential therapeutic approach for CMD in diabetes.


Apoptosis; Capillaries; Cardiovascular Disease; Coronary Blood Flow; Coronary Microcirculation


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