Although improved reperfusion strategies have led to declined mortality in non-diabetic patients after acute myocardial infarction, both prevalence and severity of post-MI heart failure (HF) continually escalates in patients with type 2 diabetes, a disease affecting >20 million people in the US. Increasing evidence demonstrates cardiometabolic dysregulation contributes significantly to HF progression. Approaches targeting more efficient substrate use and preservation of cardiac metabolism are increasingly recognized as effective therapeutic strategies against HF. Adiponectin (APN) is a novel adipokine with fundamental metabolic regulatory, anti-inflammatory, and anti-diabetic roles. Its cardioprotective roles are well-recognized both clinically and experimentally. Increasing evidence suggests biological response to APN is significantly impaired in HF patients, contributing to systemic and cardiac metabolic dysregulation and HF progression. However, mechanisms leading to impaired APN cardiovascular regulation remain unclear. Our preliminary experiments strongly support GRK2-mediated AdipoR1 phosphorylation with resultant APN signaling impairment is a significant risk factor contributing to cardiometabolic dysfunction and HF progression, particularly during diabetic conditions. This hypothesis will be rigorously investigated by identifying the specific phosphorylation sites responsible for inhibition of AdipoR1 by GRK2 (Aim 1), defining the molecular mechanisms responsible for impaired APN signaling when AdipoR1 is phosphorylated (Aim 2), and clarifying whether the molecular interventions capable of blocking AdipoR1 phosphorylation may restore cardioprotective signaling and attenuate HF progression, particularly in the diabetic heart (Aim 3). Successful completion of the proposed experiments will not only define novel molecular mechanisms leading to cardiometabolic disturbances in the failing heart, but may also identify novel targets improving cardiometabolism, attenuating HF, and reducing HF mortality, particular in diabetics. The novel data resulting from this application's proposed studies will therefore be both scientifically significant and clinically important.

Public Health Relevance

Cardiovascular complications, particularly ischemic heart disease, are primarily responsible for mortality in diabetes, a disease with alarmingly increasing prevalence that affects >20 million people in the US. Diabetic patients are at substantially increased risk for developing heart failure after a comparable initial ischemic insult, and endure poorer prognosis and increased mortality (2-6 fold) compared to non-diabetic heart failure patients. The current application endeavors to identify novel strategies capable of protecting diabetic cardiomyocytes from aggravated post- myocardial infarction injury and exacerbated heart failure progression, for the purpose of ultimately ameliorating cardiovascular disease-associated morbidity and mortality.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL096686-07
Application #
9459958
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Wong, Renee P
Project Start
2010-05-01
Project End
2020-03-31
Budget Start
2018-04-01
Budget End
2019-03-31
Support Year
7
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Thomas Jefferson University
Department
Emergency Medicine
Type
Schools of Medicine
DUNS #
053284659
City
Philadelphia
State
PA
Country
United States
Zip Code
19107
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Liu, Gai-Zhen; Liang, Bin; Lau, Wayne Bond et al. (2015) High glucose/High Lipids impair vascular adiponectin function via inhibition of caveolin-1/AdipoR1 signalsome formation. Free Radic Biol Med 89:473-85
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He, Qing; Pu, Jun; Yuan, Ancai et al. (2014) Activation of liver-X-receptor ? but not liver-X-receptor ? protects against myocardial ischemia/reperfusion injury. Circ Heart Fail 7:1032-41

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