Targeting Adiponectin for Cardioprotection in the Ischemic Heart

尽管改善的再灌注策略已导致非糖尿病患者急性心肌梗死后死亡率下降， 心肌梗死后，MI后心力衰竭（HF）的患病率和严重程度持续上升， 2型糖尿病患者，这种疾病在美国影响超过2000万人。越来越多的证据 表明心脏代谢失调显著促进HF进展。目标确定方法 更有效的底物利用和心脏代谢的保存越来越被认为是有效的 针对HF的治疗策略。脂联素（APN）是一种新的脂肪细胞因子， 调节、抗炎和抗糖尿病作用。它的心脏保护作用是公认的， 临床上和实验上。越来越多的证据表明APN的生物学反应明显受损 在HF患者中，导致全身和心脏代谢失调和HF进展。然而，在这方面， 导致APN心血管调节受损的机制仍不清楚。我们的初步实验 强烈支持GRK2介导AdipoR1磷酸化，导致APN信号传导受损， 导致心脏代谢功能障碍和HF进展的重要风险因素，尤其是在 糖尿病状况。这一假设将通过鉴定特定的磷酸化来进行严格的研究。 负责GRK2抑制AdipoR1的位点（Aim 1），定义负责的分子机制 当AdipoR1被磷酸化时，APN信号传导受损（Aim 2），并澄清是否分子 能够阻断AdipoR1磷酸化的干预可以恢复心脏保护信号， 减缓HF进展，特别是在糖尿病心脏中（目的3）。圆满完成拟议的 实验不仅将确定导致心脏代谢紊乱的新分子机制， 心力衰竭，但也可能确定新的目标，改善心脏代谢，减弱HF，并减少HF 死亡率，尤其是糖尿病患者。因此，从本申请的拟议研究中获得的新数据将 既有科学意义又有临床意义。

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.