Inflammatory Wnt signaling in ischemic myocardium

 描述（由申请人提供）：肥胖是21世纪世纪的主要全球流行病。心血管疾病（CVD）是肥胖个体死亡的主要原因。然而，脂肪组织功能障碍与CVD之间的联系机制仍不完全清楚。越来越多的证据表明，脂肪组织分泌称为脂肪因子的生物活性分子，并且由于脂肪因子分泌不平衡，肥胖导致CVD，从而产生慢性低度炎症状态。值得注意的是，我们和其他人已经表明，实验操作的脂肪因子水平可以有显着的影响，心血管疾病的过程中，在小鼠遗传模型喂养正常的食物饮食，记录的脂肪因子水平的变化足以赋予心血管功能的变化，独立于其混淆的代谢活动。我们的实验室已经确定Sfrp 5作为一种新的抗炎脂肪因子，它拮抗Wnt 5a的促炎活性，Wnt 5a是一种非经典Wnt信号转导的调节因子。虽然这些研究表明Sfrp 5/Wnt 5a轴调节脂肪组织和外周血管区室的微环境中的炎症，但其在心脏中的作用尚未探索。在这里，我们建议调查的作用，非经典Wnt 5a调节系统的发展后心肌梗死（后MI）重塑。我们假设Sfrp 5/Wnt 5a在肥胖状态下的异常调节是一种非常重要的，但以前未被认识到的代谢功能障碍促进缺血性心脏病的机制。

 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.