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

高血压是血管过早老化的一种状态，相对于实际的实际年龄。事实上，很多因素 随着我们年龄的增长，这些疾病会加速血管功能的恶化，并在高血压中加剧。 尽管如此，我们对导致动脉过早老化的机制的了解，从而增加了 高血压患者的心血管风险尚未确定。公认的是， 自噬的上调/重建可以改善衰老的表型，特别是在血管系统中。尽管如此， 自噬发挥抗血管衰老作用的确切机制仍有待阐明。因此， 该项目的长期目标是揭示自噬改善早产的新机制。 血管老化与高血压相关。在进化过程中，自噬有助于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中介。 代谢，然后可以释放底物进行酮类合成。此前，我们进行了开创性的观察 自噬诱导肝源性酮体􀈕-羟基丁酸酯(􀈕OHB)的生物合成。此外，我们还拥有 观察到􀈕oHb具有深刻的降压作用，包括有效的血管扩张。 然而，从K99期收集的数据表明，这是通过非典型信号传递的 机制。因此，我们假设肝脏中自噬的上调，刺激􀈕OHb的产生， 它诱导血管扩张，并减少与高血压相关的血管过早老化的表型。我们 我将通过执行以下具体目标来验证这一假设：1)􀈕oHb通过以下方式防止血管衰老表型 通过直接激活内皮细胞上的钾通道刺激血管扩张，以及2)减少自噬 高血压患者的活动减少􀈕-oHb的生物合成，导致高血压和血管早熟。 衰老。为了实现这些目标，我们将研究特定钾通道基因缺陷的小鼠，小鼠 自噬蛋白ATG5的遗传缺陷，以及遗传性高血压大鼠。小鼠高血压模型的建立 通过血管紧张素II输注。总的来说，这项应用提出了一种新的、生理学的机制，通过这种机制，自噬 在肝脏中防止血管过早衰老，也提出了自噬减少的致病后果 高血压时的活动性。由于血管年龄是一种新的临床使用的心血管疾病风险指标，了解 这些机制可能有助于开发新的治疗方法，以逆转或预防相关的血管损伤 患有高血压。鉴于高血压是美国主要的公共卫生负担，我们的建议非常 这在很大程度上符合美国国立卫生研究院的使命。

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.