The identification of the mechanisms predisposing to stroke may improve its preventive and therapeutic strategies in patients with essential hypertension. The role of macroautophagy/autophagy in the development of hypertension-related stroke needs to be clarified. We hypothesized that a defective autophagy may favor hypertension-related spontaneous stroke by promoting mitochondrial dysfunction. We studied autophagy in the stroke-prone spontaneously hypertensive (SHRSP) rat, which represents a clinically relevant model of stroke associated with high blood pressure. We assessed autophagy, mitophagy and NAD⁺:NADH levels in brains of SHRSP and stroke-resistant SHR fed with high salt diet. Vascular smooth muscle cells silenced for the mitochondrial complex I subunit Ndufc2 gene (NADH:ubiquinone oxidoreductase subunit C2) and cerebral endothelial cells isolated from SHRSP were also used to assess autophagy/mitophagy and mitochondrial function in response to high salt levels. We found a reduction of autophagy in brains of high salt-fed SHRSP. Autophagy impairment was associated with NDUFC2 downregulation, mitochondrial dysfunction and NAD⁺ depletion. Restoration of NAD⁺ levels by nicotinamide administration reactivated autophagy and reduced stroke development in SHRSP. A selective reactivation of autophagy/mitophagy by Tat-Beclin 1 also reduced stroke occurrence, restored autophagy/mitophagy and improved mitochondrial function. Endothelial progenitor cells (EPCs) from subjects homozygous for the thymine allele variant at NDUFC2/rs11237379, which is associated with NDUFC2 deficiency and increased stroke risk, displayed an impairment of autophagy and increased senescence in response to high salt levels. EPC senescence was rescued by Tat-Beclin 1. Pharmacological activation of autophagy may represent a novel therapeutic strategy to reduce stroke occurrence in hypertension.

Abbreviations

10 VSMCs: aortic vascular smooth muscle cells; COX4I1/COX IV: cytochrome c oxidase subunit 4I1; ECs: endothelial cells; EPCs: endothelial progenitor cells; JD: Japanese-style diet; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; NAD: nicotinamide adenine dinucleotide; NDUFC2: NADH:ubiquinone oxidoreductase subunit C2; NMN: nicotinamide mononucleotide; RD: regular diet; SHRSP: stroke-prone spontaneously hypertensive rat; SHRSR: stroke-resistant spontaneously hypertensive rat.

中文翻译：

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自噬的药理学恢复减少了与高血压相关的中风的发生。

对诱发中风的机制的识别可能会改善原发性高血压患者的预防和治疗策略。需要阐明自噬/自噬在高血压相关性中风发展中的作用。我们假设有缺陷的自噬可能通过促进线粒体功能障碍而促进高血压相关的自发性中风。我们研究了中风倾向性自发性高血压（SHRSP）大鼠的自噬，该大鼠代表与高血压相关的中风的临床相关模型。我们评估了高盐饮食喂养的SHRSP和耐中风性SHR的大脑中的自噬，线粒体和NAD ⁺：NADH水平。线粒体复合体I亚基Ndufc2沉默的血管平滑肌细胞从SHRSP中分离的基因（NADH：泛醌氧化还原酶亚基C2）和脑内皮细胞也用于评估自噬/线粒体和线粒体功能对高盐水平的反应。我们发现高盐喂养的SHRSP的大脑自噬减少。自噬功能障碍与NDUFC2下调，线粒体功能障碍和NAD ⁺耗竭有关。通过施用烟酰胺恢复NAD ⁺水平可重新激活自噬并减少SHRSP中的中风发展。Tat-Beclin 1选择性重新激活自噬/线粒体也减少了中风的发生，恢复了自噬/线粒体并改善了线粒体功能。来自NDUFC2胸腺嘧啶等位基因变异纯合受试者的内皮祖细胞（EPC）/ rs11237379与NDUFC2缺乏症和中风风险增加相关，在高盐水平下表现出自噬功能受损和衰老增加。Tat-Beclin 1挽救了EPC衰老。自噬的药理激活可能代表减少高血压中风发生率的新治疗策略。

缩略语

10个VSMC：主动脉血管平滑肌细胞；COX4I1 / COX IV：细胞色素C氧化酶亚基4I1；EC：内皮细胞；EPC：内皮祖细胞；JD：日式饮食；MAP1LC3 / LC3：微管相关蛋白1轻链3；NAD：烟酰胺腺嘌呤二核苷酸；NDUFC2：NADH：泛醌氧化还原酶亚基C2；NMN：烟酰胺单核苷酸；RD：定期饮食；SHRSP：易中风的自发性高血压大鼠；SHRSR：抗中风性自发性高血压大鼠。