Diabetic cardiomyopathy (DCM) is characterized by left ventricular remodeling and dysfunction independent of atherosclerosis, coronary heart disease, or hypertension. The mechanisms responsible for this disorder are complex and poorly understood. An emerging concept is that inflammation might be linked to alteration in insulin receptor (IR) and/or insulin-like growth factor receptor (IGF-1R) signaling, thus leading to the maladaptive cardiac structural and functional consequences of DCM. However, the role of inflammatory pathways in the development of DCM is still controversial and remains to be determined. This proposal antagonizes the adverse cardiac remodeling induced during the development of DCM through inhibition of inflammatory serine proteases (ISPs) that have emerged as important regulators not only of the immune response but also in the regulation of various biological pathways involved in cardiac remodeling. We found that genetic inhibition of ISPs in-vivo attenuated IR/IGF-1R signaling down-regulation and adverse cardiac remodeling induced by DCM without affecting hyperglycemia levels. Moreover, treatment of isolated myocytes with ISPs led to IR/IGF-1R ubiquitylation and degradation through activation of E3 ubiquitin ligase Cbl and ubiquitin proteasome system (UPS), respectively. Therefore we hypothesized that ISPs, released during the development of diabetes, promote IR/IGF-1R ubiquitylation and degradation that lead overtime to myocyte death and cardiac dysfunction. This is related to the effect of ISPs on Cbl ubiquitin ligase activation and subsequent proteasomal degradation of IR/IGF-1R.
Aim 1 will determine the mechanistic role of the ubiquitin ligase Cbl and the UPS in IR/IGF-1R turnover in response to ISPs in-vitro;
Aim 2 will determine the role of Cbl inactivation in IR/IGF-1R signaling down-regulation and adverse cardiac remodeling induced by DCM; and finally Aim 3 will determine the effect of ISPs inhibition on IR/IGF-1R signaling down-regulation, Cbl activation, and myocyte loss induced by DCM. The proposed study will integrate the novel role of ISPs and ubiquitin ligase Cbl in IR/IGF-1R turnover and myocyte death that may contribute to adverse cardiac remodeling and function during the development of DCM and determine whether ISPs should be considered a new target for therapy to treat patients with DCM.

Public Health Relevance

Cardiovascular disease, including heart failure, is the major cause of death in patients with diabetes. A contributing factor to heart failure in such patients i the development of diabetic cardiomyopathy. Several advances in the treatment of patients with diabetic cardiomyopathy have improved survival. However, this disease process is still pre-eminent in affecting the morbidity and mortality of patients with diabetes. The final goal of this project is to explore the mechanisms that lead to diabetes and to use this understanding to uncover new disease mechanisms and therapeutic approaches to prevent diabetic cardiomyopathy in humans.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Myocardial Ischemia and Metabolism Study Section (MIM)
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Chen, Jue
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Thomas Jefferson University
United States
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Shukla, Sanket Kumar; Liu, Weijing; Sikder, Kunal et al. (2017) HMGCS2 is a key ketogenic enzyme potentially involved in type 1 diabetes with high cardiovascular risk. Sci Rep 7:4590