McAllister Heart Institute University of North Carolina School of Medicine , Chapel Hill, North Carolina.
Immunity, Inflammation and Disease Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health , Research Triangle Park, North Carolina.
Am J Physiol Heart Circ Physiol. 2019 Jan 1;316(1):H186-H200. doi: 10.1152/ajpheart.00531.2018. Epub 2018 Nov 2.
The nuclear receptor retinoic acid-related orphan receptor-α (RORα) regulates numerous critical biological processes, including central nervous system development, lymphocyte differentiation, and lipid metabolism. RORα has been recently identified in the heart, but very little is known about its role in cardiac physiology. We sought to determine whether RORα regulates myocardial hypertrophy and cardiomyocyte survival in the context of angiotensin II (ANG II) stimulation. For in vivo characterization of the function of RORα in the context of pathological cardiac hypertrophy and heart failure, we used the "staggerer" (RORα) mouse, which harbors a germline mutation encoding a truncated and globally nonfunctional RORα. RORα and wild-type littermate mice were infused with ANG II or vehicle for 14 days. For in vitro experiments, we overexpressed or silenced RORα in neonatal rat ventricular myocytes (NRVMs) and human cardiac fibroblasts exposed to ANG II. RORα mice developed exaggerated myocardial hypertrophy and contractile dysfunction after ANG II treatment. In vitro gain- and loss-of-function experiments were consistent with the discovery that RORα inhibits ANG II-induced pathological hypertrophy and cardiomyocyte death in vivo. RORα directly repressed IL-6 transcription. Loss of RORα function led to enhanced IL-6 expression, proinflammatory STAT3 activation (phopho-STAT3 Tyr), and decreased mitochondrial number and function, oxidative stress, hypertrophy, and death of cardiomyocytes upon ANG II exposure. RORα was less abundant in failing compared with nonfailing human heart tissue. In conclusion, RORα protects against ANG II-mediated pathological hypertrophy and heart failure by suppressing the IL-6-STAT3 pathway and enhancing mitochondrial function. NEW & NOTEWORTHY Mice lacking retinoic acid-related orphan receptor-α (RORα) develop exaggerated cardiac hypertrophy after angiotensin II infusion. Loss of RORα leads to enhanced IL-6 expression and NF-κB nuclear translocation. RORα maintains mitochondrial function and reduces oxidative stress after angiotensin II. The abundance of RORα is reduced in failing mouse and human hearts.
核受体维甲酸相关孤儿受体-α（RORα）调节许多关键的生物学过程，包括中枢神经系统发育、淋巴细胞分化和脂质代谢。RORα 最近在心脏中被发现，但对其在心脏生理学中的作用知之甚少。我们试图确定 RORα 是否在血管紧张素 II（ANG II）刺激的情况下调节心肌肥大和心肌细胞存活。为了在病理性心肌肥大和心力衰竭的背景下对 RORα 的功能进行体内表征，我们使用了“ staggerer”（RORα）小鼠，该小鼠具有编码截短且全局无功能的 RORα 的种系突变。RORα 和野生型同窝小鼠接受 ANG II 或载体输注 14 天。对于体外实验，我们在暴露于 ANG II 的新生大鼠心室肌细胞（NRVM）和人心房成纤维细胞中过表达或沉默 RORα。RORα 小鼠在 ANG II 处理后发生明显的心肌肥大和收缩功能障碍。体内增益和失能实验与发现 RORα 抑制 ANG II 诱导的病理性肥大和心肌细胞死亡一致。RORα 直接抑制 IL-6 转录。RORα 功能丧失导致 IL-6 表达增加、促炎 STAT3 激活（磷酸-STAT3 Tyr）以及暴露于 ANG II 时线粒体数量和功能、氧化应激、肥大和心肌细胞死亡减少。与非衰竭的人心肌组织相比，衰竭的人心肌组织中 RORα 的含量较少。总之，RORα 通过抑制 IL-6-STAT3 通路和增强线粒体功能来防止 ANG II 介导的病理性肥大和心力衰竭。新的和值得注意的是，缺乏维甲酸相关孤儿受体-α（RORα）的小鼠在血管紧张素 II 输注后会发生明显的心脏肥大。RORα 的缺失会导致 IL-6 表达增强和 NF-κB 核易位。RORα 在血管紧张素 II 后维持线粒体功能并减少氧化应激。在衰竭的小鼠和人心肌中，RORα 的丰度降低。
