BACKGROUND & AIMS:
:Our hypothesis is that Secreted Frizzled-Related Protein 2 (sFPR2) is an important mechanism mediating ischemic cardioprotection, since it is the most upregulated gene in the third window of ischemic preconditioning. One week after permanent coronary artery occlusion (CAO), sFRP2 TG mice exhibited a 49% higher LV ejection fraction and a 36% reduction in infarct size, p < 0.05, and reduced fibrosis in both adjacent and remote zones, along with an increase in collagen type III and a decrease in the collagen type I/III ratio compared with WTL. The ischemic cardioprotection was associated with increased angiogenesis and arteriogenesis, reflected by increased capillary and arteriolar proliferation in the ischemic zone, thereby preserving blood flow after CAO. The angiogenesis and arteriogenesis were mediated by cross talk between myocytes and endothelial cells. The mechanism for cardioprotection and angiogenesis/arteriogenesis did not involve a traditional vascular growth hormone, e.g., VEGF or FGF, but rather cTGF, and ATF6 through the stress signaling pathway. The ATF6 inhibitor, AEBSF, blocked the upregulation of cTGF and both the angiogenesis and arteriogenesis, resulting in abolition of the reduced infarct size and protection of cardiac function in the sFRP2 TG mouse following permanent CAO. sFRP2 is a novel mechanism to induce angiogenesis/arteriogenesis, mediated through the endoplasmatic reticulum (ER) stress signaling pathway, ATF6 and cTGF, which protects the heart from myocardial ischemia.
背景与目标:
: 我们的假设是,分泌的卷曲相关蛋白2 (sFPR2) 是介导缺血性心脏保护的重要机制,因为它是缺血预处理第三窗口中上调最多的基因。永久性冠状动脉闭塞 (CAO) 一周后,sFRP2 TG小鼠表现出49% 较高的左室射血分数,梗死面积36% 减少,p < 0.05,邻近和偏远地区的纤维化减少,与WTL相比,随着III型胶原的增加和I/III型胶原比例的降低。缺血心脏保护与血管生成和动脉生成增加有关,这反映在缺血区域的毛细血管和小动脉增殖增加,从而保留了CAO后的血流。血管生成和动脉生成是由心肌细胞和内皮细胞之间的串扰介导的。心脏保护和血管生成/动脉生成的机制不涉及传统的血管生长激素,例如VEGF或FGF,而是cTGF和ATF6通过应激信号通路。ATF6抑制剂AEBSF阻止了cTGF的上调以及血管生成和动脉生成,从而消除了永久性CAO后sFRP2 TG小鼠的梗死面积减少并保护了心脏功能。sFRP2是一种通过内质网 (ER) 应激信号通路ATF6和cTGF介导的诱导血管生成/动脉生成的新机制,可保护心脏免受心肌缺血的侵害。