Inflammatory Wnt signaling in ischemic myocardium

 描述(申请人提供)：肥胖症是21世纪的主要世界性流行病。心血管疾病(CVD)是肥胖者死亡的主要原因。然而，将脂肪组织功能障碍与心血管疾病联系起来的机制仍不完全清楚。越来越多的证据表明，脂肪组织会分泌称为脂肪因子的生物活性分子，肥胖会由于脂肪因子分泌失衡而导致心血管疾病，从而造成慢性低度炎症状态。值得注意的是，我们和其他人已经证明，在喂食正常饮食的小鼠遗传模型中，对脂肪因子水平的实验性操作可以对心血管疾病过程产生显著影响，证明脂肪因子水平的变化足以导致心血管功能的变化，而不是它令人困惑的代谢作用。本实验室已确定Sfrp5是一种新的抗炎脂肪因子，它拮抗Wnt5a的促炎活性，Wnt5a是非典范Wnt信号的调节因子。虽然这些研究表明，Sfrp5/Wnt5a轴调节脂肪组织微环境和外周血管间的炎症，但它在心脏中的作用仍不清楚。在这里，我们建议研究非规范的WNT5a调节系统在发展的心肌梗死后(后MI)重构中的作用。我们假设，肥胖状态下Sfrp5/Wnt5a的异常调节是代谢功能障碍促进缺血性心脏病的一个非常重要但以前未被认识到的机制。

 DESCRIPTION (provided by applicant): Obesity is the major worldwide epidemic of the 21st century. Cardiovascular disease (CVD) is the predominant cause of mortality in obese individuals. However, the mechanisms that link adipose tissue dysfunction to CVD remain incompletely understood. A growing body of evidence shows that adipose tissue secretes bioactive molecules called adipokines, and that obesity contributes to CVD due to unbalanced adipokine secretion, creating a chronic low-grade inflammatory state. Notably, we and others have shown that experimental manipulations of adipokine levels can have marked effects on cardiovascular disease processes in mouse genetic models fed a normal chow diet, documenting that changes in adipokine levels are sufficient to confer changes in cardiovascular function independent of its confounding metabolic actions. Our laboratory has identified Sfrp5 as a new anti-inflammatory adipokine, which antagonizes the pro-inflammatory activity of Wnt5a, a regulator of non-canonical Wnt signaling. While these studies showed that the Sfrp5/Wnt5a axis modulates inflammation in the microenvironment of adipose tissue and the peripheral vascular compartment, its actions in the heart remain unexplored. Here, we propose to investigate the role of the non-canonical Wnt5a regulatory system in the development post-myocardial infarction (post-MI) remodeling. We hypothesize that the aberrant regulation of Sfrp5/Wnt5a in the obese state is a highly significant, but previously unrecognized, mechanism by which metabolic dysfunction promotes ischemic heart disease.