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

自噬调节β-羟基丁酸合成以预防高血压相关的血管过早老化

• 批准号: 10516445
• 负责人: Cameron McCarthy
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10516445
• 关键词: Autophagy; regulates; hydroxybutyrate; synthesis; prevent

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.

相对于实际年代年龄，高血压是过早血管衰老的条件。实际上，许多因素 随着年龄的增长，这有助于血管功能的定义，并在高血压中加剧和加剧。 但是，我们对导致动脉过早年龄的机制的理解，从而增加 高血压患者的心血管风险尚未确定。众所周知， 自噬的上调/重建可以改善老化的表型，尤其是在脉管系统中。尽管如此， 自噬出口抗血管老化作用的确切机制仍有待阐明。所以， 该项目的长期目标是揭示自动噬来改善早产的新型机制 与高血压相关的血管衰老。进化上，自噬可动员宏观和微量营养素 在饥饿和压力的时期。结果，自噬也被认为是肝脂质的介体 代谢，它可以解放酮基底物以进行生酮发生。以前，我们进行了第二个观察， 自噬诱导了活酮体的生物合成OHB（OHB）。此外，我们还有 观察到◎ohb具有深刻的抗高血压作用，包括分离抗性的有效血管舒张 然而，动脉从K99阶段收集的数据表明，这是通过非规范信号传导 机制。因此，我们假设肝脏自噬的上调刺激了◎OHB的产生， 这会诱导血管舒张，并增加与高血压相关的过早血管衰老的表型。我们 将通过执行以下特定目的来检验这一假设：1）OHB通过 通过直接激活内皮细胞上的钾通道来刺激血管舒张，2）精制自噬 高血压的活性降低了OHB生物合成，有助于高血压和过早血管 老化。为了执行这些目标，我们将研究小鼠在特定钾通道中的小鼠，小鼠 在遗传上缺乏自噬蛋白ATG5和遗传性高血压大鼠。小鼠将诱导高血压 通过血管紧张素II输注。总的来说，该应用程序提出了一种新颖的生理机制，该机制是自噬的 在肝脏中可防止过早的血管老化，还提出了自噬减少的致病结果 高血压的活性。由于血管年龄是一种新的临床使用指数，用于心血管疾病风险，因此了解 这些机制可能有助于开发新的疗法，以逆转或预防与血管损伤相关 高血压。鉴于高血压是美国的主要公共卫生伯恩顿，我们的提议非常 与国家卫生研究院的使命相符。