NAT10 in Cardiac Response to Exercise in Diabetes
Description: Diabetic cardiomyopathy is a major complication and one of the leading causes of death and disability in patients with diabetes. Effective treatment to improve outcomes is lacking, and prognosis remains poor for patients with diabetic cardiomyopathy. Thus, there is a growing unmet clinical need for novel therapeutic approaches in diabetic cardiomyopathy. Exercise is an effective strategy for the prevention and treatment of diabetic cardiomyopathy, however, the underlying molecular mechanisms remain poorly understood. N4-acetylcytidine (ac4C) has emerged as a key posttranscriptional gene regulation in diseases. N-acetyltransferase (NAT10) is the only known ac4C writer enzyme. NAT10 has been implicated in myocardial ischemia injury, heart failure, and vascular aging. However, little is known about the role of NAT10 in diabetic cardiomyopathy and the cardiac benefits of exercise in diabetes. Our preliminary studies found that cardiac NAT10 is downregulated in diabetes and is upregulated by exercise. Further, cardiomyocyte-specific knockout of NAT10 cancels the beneficial effects of exercise on hearts from diabetes. ac4C sequencing in combination with proteomics analysis identifies HSP27 as a downstream target of NAT10. We hypothesize that NAT10 is sufficient and necessary for exercise’s beneficial effects in protecting the heart against diabetic cardiomyopathy, and that it does so through HSP27. We will test this hypothesis with three specific aims: (1) to examine the effects of NAT10 on diabetic cardiomyopathy, (2) to determine the role of NAT10 in cardiac response to exercise in diabetes, and (3) to elucidate the mechanisms by which NAT10 regulates diabetic cardiomyopathy. We anticipate that these studies will shed new light on the role of ac4C (e.g., NAT10) in the pathophysiology of diabetic cardiomyopathy. Moreover, these studies will establish clinically relevant approaches targeting NAT10/HSP27 to combat cardiomyopathy in patients with diabetes.
Funder: American Heart Association
Amount: $300,000
Funding type: research
Funder scheme: Second Century Early Faculty Independence Award
Start date: 2024-04-01
End date: 2027-03-31
Investigators: Haobo Li, Haobo Li
Institution: Massachusetts General Hospital (Mass General)
Funded outputs count: 10
Funder award ID: 24SCEFIA1253853
OpenAlex ID: G1881849442