Cowley Patrick M, Wang Guanying, Joshi Sunil, Swigart Philip M, Lovett David H, Simpson Paul C, Baker Anthony J
Veterans Affairs Medical Center, San Francisco, California, and Department of Medicine, University of California, San Francisco, California.
Veterans Affairs Medical Center, San Francisco, California, and Department of Medicine, University of California, San Francisco, California
Am J Physiol Heart Circ Physiol. 2017 Dec 1;313(6):H1109-H1118. doi: 10.1152/ajpheart.00153.2017. Epub 2017 Aug 19.
Failure of the right ventricle (RV) is a serious disease with a poor prognosis and limited treatment options. Signaling by α-adrenergic receptors (α-ARs), in particular the α-subtype, mediate cardioprotective effects in multiple heart failure models. Recent studies have shown that chronic treatment with the α-subtype agonist A61603 improves function and survival in a model of left ventricular failure. The goal of the present study was to determine if chronic A61603 treatment is beneficial in a RV failure model. We used tracheal instillation of the fibrogenic antibiotic bleomycin in mice to induce pulmonary fibrosis, pulmonary hypertension, and RV failure within 2 wk. Some mice were chronically treated with a low dose of A61603 (10 ng·kg·day). In the bleomycin model of RV failure, chronic A61603 treatment was associated with improved RV fractional shortening and greater in vitro force development by RV muscle preparations. Cell injury markers were reduced with A61603 treatment (serum cardiac troponin I, RV fibrosis, and expression of matrix metalloproteinase-2). RV oxidative stress was reduced (using the probes dihydroethidium and 4-hydroxynonenal). Consistent with lowered RV oxidative stress, A61603 was associated with an increased level of the cellular antioxidant superoxide dismutase 1 and a lower level of the prooxidant NAD(P)H oxidase isoform NOX4. In summary, in the bleomycin model of RV failure, chronic A61603 treatment reduced RV oxidative stress, RV myocyte necrosis, and RV fibrosis and increased both RV function and in vitro force development. These findings suggest that in the context of pulmonary fibrosis, the α-subtype is a potential therapeutic target to treat the failing RV. Right ventricular (RV) failure is a serious disease with a poor prognosis and no effective treatments. In the mouse bleomycin model of RV failure, we tested the efficacy of a treatment using the α-adrenergic receptor subtype agonist A61603. Chronic A61603 treatment improved RV contraction and reduced multiple indexes of RV injury, suggesting that the α-subtype is a therapeutic target to treat RV failure.
右心室（RV）衰竭是一种严重疾病，预后不良且治疗选择有限。α-肾上腺素能受体（α-ARs），特别是α亚型的信号传导，在多种心力衰竭模型中介导心脏保护作用。最近的研究表明，用α亚型激动剂A61603进行长期治疗可改善左心室衰竭模型中的功能和生存率。本研究的目的是确定长期A61603治疗对RV衰竭模型是否有益。我们通过气管内滴注致纤维化抗生素博来霉素诱导小鼠肺纤维化、肺动脉高压和2周内的RV衰竭。一些小鼠用低剂量的A61603（10 ng·kg·天）进行长期治疗。在博来霉素诱导的RV衰竭模型中，长期A61603治疗与RV缩短分数的改善以及RV肌肉制剂体外力量发展的增强有关。A61603治疗可降低细胞损伤标志物（血清心肌肌钙蛋白I、RV纤维化和基质金属蛋白酶-2的表达）。RV氧化应激降低（使用二氢乙锭和4-羟基壬烯醛探针）。与降低的RV氧化应激一致，A61603与细胞抗氧化剂超氧化物歧化酶1水平升高和促氧化剂NAD(P)H氧化酶亚型NOX4水平降低有关。总之，在博来霉素诱导的RV衰竭模型中，长期A61603治疗可降低RV氧化应激、RV心肌细胞坏死和RV纤维化，并增加RV功能和体外力量发展。这些发现表明，在肺纤维化的背景下，α亚型是治疗衰竭RV的潜在治疗靶点。右心室（RV）衰竭是一种严重疾病，预后不良且无有效治疗方法。在小鼠博来霉素诱导的RV衰竭模型中，我们测试了使用α-肾上腺素能受体亚型激动剂A61603进行治疗的疗效。长期A61603治疗改善了RV收缩并降低了RV损伤的多个指标，表明α亚型是治疗RV衰竭的治疗靶点。
