Targeting Adiponectin for Cardioprotection in the Ischemic Heart

尽管改进的再灌注策略降低了非糖尿病患者急性心肌梗死后的死亡率 心肌梗死，心肌梗死后心力衰竭(HF)的患病率和严重程度在 患有2型糖尿病的患者，这种疾病在美国影响着2000万人。越来越多的证据 证明心脏代谢失调对心力衰竭的进展有重要作用。针对目标的方法 更有效地利用底物和保存心脏代谢越来越被认为是有效的 抗心衰的治疗策略。脂联素(APN)是一种具有基础代谢功能的新型脂肪因子 具有调节、抗炎和抗糖尿病的作用。它的心脏保护作用是公认的 临床和实验上都是如此。越来越多的证据表明，对APN的生物反应明显受损 在心力衰竭患者中，导致全身和心脏代谢紊乱和心力衰竭进展。然而， 导致APN心血管调节受损的机制尚不清楚。我们的初步实验 强烈支持GRK2介导的AdipoR1磷酸化以及由此导致的APN信号损伤是一种 导致心脏代谢功能障碍和心力衰竭进展的重要危险因素，特别是在 糖尿病的情况。将通过鉴定特定的磷酸化来严格研究这一假说。 负责GRK2抑制AdipoR1的位点(目标1)，定义了相关的分子机制 当AdipoR1被磷酸化时，APN信号受损(目标2)，并澄清分子是否 能够阻断AdipoR1磷酸化的干预措施可能会恢复心脏保护信号和 延缓心衰进展，特别是在糖尿病心脏(目标3)。圆满完成拟议中的 实验不仅将定义导致心脏代谢障碍的新的分子机制 心力衰竭，但也可能确定改善心脏代谢、减轻心力衰竭和降低心力衰竭的新靶点 死亡率，特别是在糖尿病患者中。因此，由本申请提议的研究产生的新数据将 既具有科学意义，又具有临床重要性。

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.