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

基本信息

项目摘要

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.
高血压是一种相对于实际年龄而言血管过早老化的病症。其实很多因素 随着年龄的增长,导致血管功能恶化的因素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了解,从而增加了 高血压患者的心血管风险尚未确定。众所周知, 自噬的上调/重建可改善衰老表型,尤其是在脉管系统中。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。所以, 该项目的长期目标是揭示自噬改善过早衰老的新机制 血管老化与高血压有关。从进化角度来看,自噬可以调动大量营养素和微量营养素 在饥饿和压力时期。因此,自噬也被认为是肝脂质的介质 新陈代谢,然后可以释放生酮的底物。之前,我们做了一个开创性的观察: 自噬诱导肝源性酮体、羟基丁酸(OHB)的生物合成。此外,我们还有 观察到,OHB 具有深远的抗高血压作用,包括对孤立阻力的有效血管舒张作用 然而,从 K99 阶段收集的数据表明,这是通过非规范信号传导实现的 机制。因此,我们假设肝脏中自噬的上调会刺激OHB的产生, 它诱导血管舒张,并减少与高血压相关的血管过早老化的表型。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,2) 减少自噬 高血压患者的活动会减少OHB生物合成,导致高血压和血管早发 老化。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,小鼠 自噬蛋白 Atg5 遗传缺陷和遗传性高血压大鼠。会诱发小鼠高血压 通过血管紧张素II输注。总的来说,该申请提出了一种新颖的生理机制,通过该机制自噬 在肝脏中可以防止血管过早老化,并提出自噬减少的致病后果 高血压活动。由于血管年龄是临床上新的心血管疾病风险指标,了解 这些机制可能有助于开发新疗法来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,我们的建议非常重要 很大程度上符合美国国立卫生研究院的使命。

项目成果

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Cameron McCarthy其他文献

Cameron McCarthy的其他文献

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{{ truncateString('Cameron McCarthy', 18)}}的其他基金

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
  • 财政年份:
    2022
  • 资助金额:
    $ 24.9万
  • 项目类别:

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