Stevens Sarah C W, Velten Markus, Youtz Dane J, Clark Yvonne, Jing Runfeng, Reiser Peter J, Bicer Sabahattin, Devine Raymond D, McCarthy Donna O, Wold Loren E
Center for Cardiovascular and Pulmonary Research, The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA.
Department of Anesthesiology and Intensive Care Medicine, Rheinische Friedrich-Wilhelms-University, University Medical Center, Bonn, Germany.
J Mol Cell Cardiol. 2015 Aug;85:37-47. doi: 10.1016/j.yjmcc.2015.05.007. Epub 2015 May 16.
Fatigue and muscle wasting are common symptoms experienced by cancer patients. Data from animal models demonstrate that angiotensin is involved in tumor-induced muscle wasting, and that tumor growth can independently affect myocardial function, which could contribute to fatigue in cancer patients. In clinical studies, inhibitors of angiotensin converting enzyme (ACE) can prevent the development of chemotherapy-induced cardiovascular dysfunction, suggesting a mechanistic role for the renin-angiotensin-aldosterone system (RAAS). In the present study, we investigated whether an angiotensin (AT) 1-receptor antagonist could prevent the development of tumor-associated myocardial dysfunction.
Colon26 adenocarcinoma (c26) cells were implanted into female CD2F1 mice at 8weeks of age. Simultaneously, mice were administered Losartan (10mg/kg) daily via their drinking water. In vivo echocardiography, blood pressure, in vitro cardiomyocyte function, cell proliferation assays, and measures of systemic inflammation and myocardial protein degradation were performed 19days following tumor cell injection. Losartan treatment prevented tumor-induced loss of muscle mass and in vitro c26 cell proliferation, decreased tumor weight, and attenuated myocardial expression of interleukin-6. Furthermore, Losartan treatment mitigated tumor-associated alterations in calcium signaling in cardiomyocytes, which was associated with improved myocyte contraction velocity, systolic function, and blood pressures in the hearts of tumor-bearing mice.
These data suggest that Losartan may mitigate tumor-induced myocardial dysfunction and inflammation.
疲劳和肌肉萎缩是癌症患者常见的症状。动物模型数据表明，血管紧张素参与肿瘤诱导的肌肉萎缩，且肿瘤生长可独立影响心肌功能，这可能导致癌症患者出现疲劳。在临床研究中，血管紧张素转换酶（ACE）抑制剂可预防化疗引起的心血管功能障碍，提示肾素-血管紧张素-醛固酮系统（RAAS）具有机制性作用。在本研究中，我们调查了血管紧张素（AT）1受体拮抗剂是否能预防肿瘤相关的心肌功能障碍的发生。
将结肠26腺癌（c26）细胞植入8周龄雌性CD2F1小鼠体内。同时，通过饮用水给小鼠每日灌胃氯沙坦（10mg/kg）。在肿瘤细胞注射后19天进行体内超声心动图、血压、体外心肌细胞功能、细胞增殖测定以及全身炎症和心肌蛋白降解的测量。氯沙坦治疗可预防肿瘤诱导的肌肉量减少和体外c26细胞增殖，降低肿瘤重量，并减弱心肌白细胞介素-6的表达。此外，氯沙坦治疗减轻了肿瘤相关的心肌细胞钙信号改变，这与荷瘤小鼠心脏中肌细胞收缩速度、收缩功能和血压的改善有关。
这些数据表明氯沙坦可能减轻肿瘤诱导的心肌功能障碍和炎症。
