Dietary restriction promotes vascular health through hydrogen sulfide-mediated angiogenesis

项目摘要 饮食限制通过硫化氢介导的血管生成促进血管健康 衰老是心血管疾病、神经退行性疾病和II型糖尿病的主要危险因素， 其涉及脉管系统、血管和毛细血管系统的进行性功能障碍， 将血液输送到全身。维持血管健康预计将产生重大的有益影响 关于健康和寿命。血管生成，或从现有的血管内皮细胞生长新的血管。 血管，是一个过程，通过它可以维持或改善血管健康和功能。血管生成是 在正常的生理情况下，如运动，但也由病理生理刺激触发 包括由于血管阻塞引起的局部缺血。在这两种情况下，缺氧都是导致 通过激活缺氧诱导因子1 α控制的遗传程序的血管生成 (HIF1α）转录因子。 饮食限制，一般定义为减少食物摄入量而不营养不良，延长寿命， 健康寿命和抗应激能力的实验生物，但潜在的细胞和分子 其机制在很大程度上仍然未知，特别是在哺乳动物中。我们令人惊讶的初步数据表明， 营养限制可以通过一种新的机制促进血管生成，而不依赖于缺氧或HIF 1 α。 具体来说，我们发现，仅限制含硫氨基酸蛋氨酸和半胱氨酸， 也被称为甲硫氨酸限制的方案强烈增加了小鼠的肌肉毛细血管密度。这 通过激活氨基酸剥夺传感器GCN 2和下游转录发生 ATF 4因子。它还需要另一个下游ATF 4靶点，转硫途径基因CGL， 内源性硫化氢（H2S）的主要生产者。H2S的增加反过来又是血管生成所必需的。 通过一种新的机制，涉及从氧化代谢到糖酵解代谢的代谢转换。 在这里，我们建议测试的假设，饮食限制一般，和蛋氨酸限制， 特别是，通过一种新的血管生成途径增加血管生成， 需要CGL和H2S的机制。我们将测试增加血管生成的功能后果， 血管功能/功能障碍的标准啮齿动物临床前模型，以及其对寿命的贡献 通过饮食限制来延长寿命。总之，我们期望发现控制血管生成的新途径 和血管功能的潜力，以翻译到人类的背景下，老化和老化相关的 紊乱

PROJECT SUMMARY Title: Dietary restriction promotes vascular health through hydrogen sulfide-mediated angiogenesis Aging is a prime risk factor for cardiovascular disease, neurodegenerative disease and type II diabetes, all of which involve progressive dysfunction of the vasculature, the system of blood vessels and capillaries that deliver blood throughout the body. Maintenance of vascular health is expected to have major beneficial effects on healthspan and lifespan. Angiogenesis, or the growth of new blood vessels from endothelial cells in existing vessels, is a process by which vascular health and function can be maintained or improved. Angiogenesis is triggered under normal physiological situations such as exercise, but also by pathophysiological stimuli including ischemia due to blockage of a blood vessel. In both cases, oxygen deprivation is a major trigger of angiogenesis through activation of a genetic program controlled by the hypoxia inducible factor 1 alpha (HIF1α) transcription factor. Dietary restriction, generally defined as reduced food intake without malnutrition, increases lifespan, healthspan and stress resistance in experimental organisms, but the underlying cellular and molecular mechanisms remain largely unknown, particularly in mammals. Our surprising preliminary data indicate that nutrient restriction can promote angiogenesis via a novel mechanism independent of hypoxia or HIF1 α. Specifically, we found that restriction of just the sulfur-containing amino acids methionine and cysteine, a regimen also known as methionine restriction, strongly increased muscle capillary density in mice. This occurred through the activation of the amino acid deprivation sensor GCN2 and the downstream transcription factor ATF4. It also required another downstream ATF4 target, the transsulfuration pathway gene CGL, a major producer of endogenous hydrogen sulfide (H2S). Increased H2S was in turn required for angiogenesis through a novel mechanism involving a metabolic switch from oxidative to glycolytic metabolism. Here, we propose to test the hypothesis that dietary restriction in general, and methionine restriction in particular, increases lifespan and healthspan of rodents in part by increasing angiogenesis via a novel mechanism requiring CGL and H2S. We will test the functional consequences of increased angiogenesis in standard rodent preclinical models of vascular function/dysfunction, as well as its contribution to lifespan extension by dietary restriction. Taken together, we expect to uncover novel pathways controlling angiogenesis and vascular function with the potential to translate to humans in the context of aging and aging-related disorders.