Diabetes mellitus is strongly associated with vascular complications in many vascular beds, resulting in enormous costs to the individuals and to the society of the United States. Coronary BK channels are the key determinant of and coronary blood flow and cardiac perfusion, which are diminished in diabetes. We have demonstrated that coronary BK channel malfunction is mainly due to increased BK channel beta-1 subunit (BK-beta-1) protein degradation in response to oxidative stress, which contributes to diabetic vascular complications in diabetic animals. The Nrf2 signaling pathway plays a pivotal role in the maintenance of intracellular redox homeostasis. However, Nrf2 protein expression is down regulated in type 2 diabetic animal vessels. We have substantial preliminary results indicating that Nrf2 is critical for BK-beta-1 expression and vascular BK channel function, but underlying mechanism remains unclear. Most importantly, we have yet to elucidate whether these BK channel abnormities observed in animal studies can be reproduced in type 2 diabetic patients. In this project, we will take advantage of available human heart tissues from type 2 diabetic patients who undergo cardiac surgery and FDA-approved Nrf2 activators to delineate the role of Nrf2 signaling in the regulation of coronary BK channel function and coronary vasodilation, particularly in type 2 diabetic patients, and to further evaluate whether targeting Nrf2 signaling is a viable therapeutic strategy in the prevention and treatment of cardiovascular complications in diabetic patients. The long-term goal is to develop novel modalities of clinical therapy to improve the quality of life in patients with diabetes.
|Effective start/end date||1/1/16 → 12/31/18|
- American Diabetes Association
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