Autophagy regulates β-hydroxybutyrate synthesis to prevent hypertension-associated premature vascular aging

高血压是一种血管相对于实际年龄过早老化的疾病。事实上， 随着年龄的增长，血管功能的恶化在高血压中会加速和加剧。 尽管如此，我们对导致动脉过早老化的机制的理解， 高血压患者的心血管风险尚未确定。众所周知， 自噬的上调/重建改善了衰老表型，特别是在脉管系统中。尽管如此， 自噬发挥抗血管老化作用的精确机制仍有待阐明。因此，我们认为， 该项目的长期目标是揭示自噬改善早产儿的新机制， 与高血压相关的血管老化。从进化的角度来看，自噬可以调动大量和微量营养素 在饥饿和压力的时候。因此，自噬也被认为是肝脏脂质的介质 代谢，然后可以释放酮生成的底物。在此之前，我们进行了开创性的观察， 自噬诱导肝源性酮体β-羟基丁酸酯（β-OHB）的生物合成。此外，我们有 观察到OHB具有深刻的抗高血压作用，包括对孤立阻力的有效血管舒张作用 然而，从K99期收集的数据表明，这是通过一个非经典的信号传导， 机制因此，我们假设肝脏中自噬的上调刺激了β-羟丁酸的产生， 其诱导血管舒张并降低与高血压相关的过早血管老化的表型。我们 将通过执行以下具体目标来检验这一假设：1）OHB通过以下方式预防血管老化表型： 通过直接激活内皮细胞上的钾通道刺激血管舒张，和2）降低自噬性 高血压中的活性降低了β-羟丁酸的生物合成，导致高血压和过早的血管新生。 衰老为了实现这些目标，我们将研究特定钾通道遗传缺陷的小鼠， 自噬蛋白Atg 5基因缺陷的大鼠和遗传性高血压大鼠。将在小鼠中诱导高血压 通过血管紧张素II输注。总的来说，本申请提出了一种新的生理机制， 防止过早的血管老化，也提出了自噬减少的致病后果， 高血压的活动。由于血管年龄是临床上用于心血管疾病风险的新指标， 这些机制可能有助于开发新的治疗方法来逆转或预防血管损伤 高血压鉴于高血压是美国主要的公共卫生负担，我们的建议非常重要。 这与美国国立卫生研究院的使命非常一致。

Hypertension is a condition of premature vascular aging, relative to actual chronological age. In fact, many factors that contribute to the deterioration of vascular function as we age are accelerated and exacerbated in hypertension. Nonetheless, our understanding of the mechanisms that cause arteries to prematurely age, thus increasing the cardiovascular risk for hypertensive patients, is yet to be determined. It is well established that the upregulation/reconstitution of autophagy ameliorates the aged phenotype, especially in the vasculature. Nonetheless, the precise mechanisms by which autophagy exerts anti-vascular aging effects, remain to be elucidated. Therefore, the long-term objective of this project is to uncover novel mechanisms by which autophagy ameliorates premature vascular aging associated with hypertension. Evolutionarily, autophagy serves to mobilize macro - and micronutrients in times of starvation and stress. As a result, autophagy has also been recognized as a mediator of hepatic lipid metabolism, which could then liberate substrates for ketogenesis. Previously, we made the seminal observation that autophagy induces the biosynthesis of liver-derived ketone body, 􀈕-hydroxybutyrate (􀈕OHB). Furthermore, we have observed that 􀈕OHB has profound anti-hypertensive effects, including potent vasodilation of isolated resistance arteries, however, data collected from the K99 phase has suggested that this is through a non -canonical signaling mechanism. Therefore, we hypothesize that upregulation of autophagy in liver, stimulates the production of 􀈕OHB, which induces vasodilation, and decreases phenotypes of premature vascular aging associated with hypertension. We will test this hypothesis by executing the following specific aims: 1) 􀈕OHB prevents vascular aging phenotypes by stimulating vasodilation via direct activation of potassium channels on endothelial cells, and 2) decreased autophagic activity in hypertension reduces 􀈕OHB biosynthesis, contributing to high blood pressure and premature vascular aging. To execute these aims, we will investigate mice genetically deficient in specific potassium channels, mice genetically deficient in autophagy protein Atg5, and genetically hypertensive rats. Hypertension will be induced in mice via angiotensin II infusion. Collectively, this application proposes a novel, physiologic mechanism by which autophagy in the liver prevents premature vascular aging and also proposes a pathogenic consequence of decreased autophagic activity in hypertension. As vascular age is a new clinically used index for cardiovascular disease risk, understanding these mechanisms may assist in the development of new therapies to reverse or prevent vascular damage associated with hypertension. Given that hypertension is a major public health burden in the United States, our proposal is very much in accordance with the mission of the National Institutes of Health.