Renovascular hypertension induces myocardial mitochondrial damage, contributing to cardiac injury and dysfunction in pigs with metabolic syndrome.
Renovascular hypertension induces myocardial mitochondrial damage, contributing to cardiac injury and dysfunction in pigs with metabolic syndrome.
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DOI：
10.1093/ajh/hpaa202
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发表时间：
2020-12
影响因子：
3.2
通讯作者：
A. Nargesi;M. Farah;Xiang-yang Zhu;Lei Zhang;H. Tang;Kyra L. Jordan;Ishran M Saadiq;A. Lerman;L. Lerman;A. Eirin
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文献类型：
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作者：
A. Nargesi;M. Farah;Xiang-yang Zhu;Lei Zhang;H. Tang;Kyra L. Jordan;Ishran M Saadiq;A. Lerman;L. Lerman;A. Eirin
肾血管性高血压（RVH）患者通常也表现为代谢综合征（MetS）。代谢综合征和高血压并存会增加心血管疾病的发病率和死亡率，但心脏损伤的机制尚不清楚。我们假设MetS的叠加诱导心肌线粒体损伤，导致猪RVH的心脏损伤和功能障碍。方法猪在饮食诱导的MetS伴或不伴RVH（单侧肾动脉狭窄）16周后进行研究，并进行瘦对照（每组n=6）。通过多探测器CT、心脏线粒体形态学（透射电子显微镜）以及组织和分离线粒体中的心肌功能评估收缩期和舒张期心脏功能。结果MetS组的体重同样高于瘦体重组。RVH组出现显著狭窄并发展为高血压。与Lean和MetS相比，RVH组的线粒体基质密度和ATP产量较低，H2 O2产量较高。Lean+RVH（而非MetS+RVH）激活线粒体自噬，这与线粒体自噬相关microRNA的心肌表达降低相关。MetS组表现出更高数量的线粒体间连接（IMJ），这可能阻止MetS+RVH中线粒体自噬的膜去极化/激活。与Lean+RVH相比，MetS+RVH的心脏纤维化、肥大（左心室肌肉质量增加）和舒张功能（E/A比值降低）更大。结论MetS与猪RVH重叠可引起心肌线粒体损伤和功能障碍。MetS+RVH未能激活线粒体自噬，导致更严重的心脏重塑、纤维化和舒张功能障碍。线粒体损伤和受损的线粒体自噬可能是改善MetS和RVH共存患者心脏损伤和功能障碍的重要机制和潜在治疗靶点。
BACKGROUND Subjects with renovascular hypertension (RVH) often manifest with metabolic syndrome (MetS) as well. Coexisting MetS and hypertension increases cardiovascular morbidity and mortality, but the mechanisms underlying cardiac injury remain unknown. We hypothesized that superimposition of MetS induces myocardial mitochondrial damage, leading to cardiac injury and dysfunction in swine RVH. METHODS Pigs were studied after 16 weeks of diet-induced MetS with or without RVH (unilateral renal artery stenosis), and Lean controls (n=6 each). Systolic and diastolic cardiac function were assessed by multi-detector CT, and cardiac mitochondrial morphology (transmission electron microscopy) and myocardial function in tissue and isolated mitochondria. RESULTS Body weight was similarly higher in MetS groups vs. Lean. RVH groups achieved significant stenosis and developed hypertension. Mitochondrial matrix density and ATP production were lower and H2O2 production higher in RVH groups versus Lean and MetS. Lean+RVH (but not MetS+RVH) activated mitophagy, which was associated with decreased myocardial expression of mitophagy-related microRNAs. MetS groups exhibited higher numbers of inter-mitochondrial junctions (IMJs), which could have prevented membrane depolarization/activation of mitophagy in MetS+RVH. Cardiac fibrosis, hypertrophy (increased left ventricular muscle mass), and diastolic function (decreased E/A ratio) were greater in MetS+RVH versus Lean+RVH. CONCLUSIONS Superimposition of MetS on swine RVH induces myocardial mitochondrial damage and dysfunction. MetS+RVH failed to activate mitophagy, resulting in greater cardiac remodeling, fibrosis, and diastolic dysfunction. Mitochondrial injury and impaired mitophagy may constitute important mechanisms and potential therapeutic targets to ameliorate cardiac damage and dysfunction in patients with coexisting MetS and RVH.