Service of Cardiology, Cardiovascular Department, Lausanne University Hospital (CHUV) Lausanne, Switzerland.
Cardiovascular Assessment Facility, University of Lausanne, Lausanne, Switzerland.
Cardiovasc Res. 2018 Feb 1;114(2):272-281. doi: 10.1093/cvr/cvx162.
Clinical studies suggest beneficial effects of renin-angiotensin system blockade for prevention of left ventricular (LV) dysfunction after chemotherapy. However, the efficacy of this strategy as primary prevention has been poorly studied. This study aimed at identifying the pathophysiological mechanisms by which mineralocorticoid receptor antagonism (MRA) or angiotensin converting enzyme inhibition (ACEi) provide protection against doxorubicin-induced cardiotoxicity (DIC) in mouse models of acute and chronic toxicity.
Acute DIC was induced by a single injection of Dox at 15 mg/kg and chronic DIC applied 5 injections of Dox at 4 mg/kg/week. MRA was achieved using eplerenone or cardiomyocyte-specific ablation of the MR gene in transgenic mice and ACEi using enalapril. Drugs were provided with the first dose of Dox and applied until the end of the study. In both model of DIC, Dox induced cardiac atrophy with decreased LV volume, reduced cardiomyocyte cell size, and cardiac dysfunction. In the acute model, neither MRA nor ACEi protected against these manifestations of DIC. In the chronic model, concomitant treatment with eplerenone did not protect against DIC and drastically increased plasma aldosterone levels and cardiac levels of angiotensin II type 1 receptor and of connective tissue growth factor (CTGF), as observed in acute DIC. Enalapril treatment in the chronic model, however, protected against cardiac dysfunction and cardiomyocyte atrophy and was associated with increased activation of the PI3K/AKT/mTOR pathway along with normal levels of CTGF.
Enalapril and eplerenone disparately impact on cellular signalling in DIC. Eplerenone, on top of Dox treatment was not protective and associated with increased levels of plasma aldosterone and of cardiac CTGF. In contrast, we show that primary prevention with enalapril preserves LV morphology and function in a clinically relevant model of chronic DIC, with increased stimulation of the PI3K/AKT/mTOR axis and normal CTGF levels suggesting potential therapeutic implications.
临床研究表明，肾素-血管紧张素系统阻断剂有益于预防化疗后左心室（LV）功能障碍。然而，这种策略作为一级预防的疗效尚未得到充分研究。本研究旨在确定醛固酮受体拮抗剂（MRA）或血管紧张素转换酶抑制（ACEi）通过何种病理生理机制为急性和慢性毒性的多柔比星诱导的心脏毒性（DIC）提供保护。
通过单次注射 15mg/kg 的多柔比星（Dox）诱导急性 DIC，通过每周 4mg/kg 注射 5 次 Dox 诱导慢性 DIC。使用依普利酮或转基因小鼠心肌细胞特异性敲除 MR 基因实现 MRA，使用依那普利实现 ACEi。在 Dox 的第一次注射时给予药物，并在研究结束前使用。在这两种 DIC 模型中，Dox 均诱导心脏萎缩，LV 容积减少，心肌细胞体积减小，心脏功能障碍。在急性模型中，MRA 和 ACEi 均不能预防这些 DIC 表现。在慢性模型中，与依普利酮同时治疗不仅不能预防 DIC，而且会显著增加血浆醛固酮水平以及心脏中的血管紧张素 II 型 1 受体和结缔组织生长因子（CTGF）水平，这与急性 DIC 中观察到的情况相同。然而，在慢性模型中，依那普利治疗可预防心脏功能障碍和心肌细胞萎缩，并与 PI3K/AKT/mTOR 通路的激活增加以及 CTGF 水平正常相关。
依那普利和依普利酮对 DIC 中的细胞信号转导有不同的影响。与多柔比星联合治疗的依普利酮没有保护作用，且与血浆醛固酮水平升高和心脏 CTGF 水平升高有关。相反，我们表明，依那普利的原发性预防可在慢性 DIC 的临床相关模型中维持 LV 形态和功能，同时增加 PI3K/AKT/mTOR 轴的刺激作用和 CTGF 水平正常，提示可能具有治疗意义。
