Dietary restriction promotes vascular health through hydrogen sulfide-mediated angiogenesis

项目总结 标题：限制饮食通过硫化氢介导的血管生成促进血管健康 老龄化是心血管疾病、神经退行性疾病和II型糖尿病的主要风险因素，所有这些 它涉及血管系统、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 关于健康寿命和寿命。血管生成，或从现有的血管内皮细胞生长新的血管 血管，是维持或改善血管健康和功能的过程。血管生成是 在正常生理情况下触发，如运动，但也由病理生理刺激触发 包括因血管堵塞而导致的缺血。在这两种情况下，缺氧都是导致 通过激活由缺氧诱导因子1α控制的遗传程序的血管生成 (HIF1α)转录因子。 饮食限制，通常定义为在没有营养不良的情况下减少食物摄入量，延长寿命， 实验生物体的健康寿命和抗应激能力，但潜在的细胞和分子 机制在很大程度上仍不清楚，特别是在哺乳动物身上。我们令人惊讶的初步数据表明 营养限制可以通过一种不依赖于缺氧或HIF1α的新机制促进血管生成。 具体地说，我们发现，只有含硫氨基酸蛋氨酸和半胱氨酸的限制，a 该疗法也被称为蛋氨酸限制，显著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GCN2和下游转录而发生 因子ATF4。它还需要另一个下游的ATF4靶基因，即跨硫途径基因CGL，a 内源性硫化氢(H2S)的主要生产者。增加的硫化氢反过来又是血管生成所需的 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，我们建议检验这样一种假设，即一般的饮食限制和蛋氨酸限制在 特别是，延长啮齿动物的寿命和健康寿命的部分原因是通过一种新的 需要CGL和硫化氢的机理。我们将测试血管生成增加的功能后果 血管功能/功能障碍的标准啮齿动物临床前模型及其对寿命的贡献 通过饮食限制来延长。综上所述，我们希望发现控制血管生成的新途径 在老龄化和衰老相关的背景下，具有转化为人类的潜力的血管功能 精神错乱。

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.