Cyclooxygenase-2 inhibitor treatment improves left ventricular function and mortality in a murine model of doxorubicin-induced heart failure
Cyclooxygenase-2 inhibitor treatment improves left ventricular function and mortality in a murine model of doxorubicin-induced heart failure
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DOI：
10.1161/01.cir.0000121354.34067.48
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发表时间：
2004-03-23
期刊：
影响因子：
37.8
通讯作者：
Willerson, JT
中科院分区：
文献类型：
--
作者：
Delgado, RM;Nawar, MA;Willerson, JT
背景——初始心肌损伤后心力衰竭的进展部分是由多种冗余炎症介质介导的，包括广泛表达的环氧化酶-2 （COX-2）。由于COX-2抑制剂在治疗许多炎症介导的疾病中是有用的，我们想知道COX-2抑制剂是否可以减轻心力衰竭的进展。方法与结果：用阿霉素（4mg）诱导100只小鼠心力衰竭。公斤(1)。周（-1）为6周。从第42天开始，每天给小鼠喂食含COX-2抑制剂的小鼠饲料（n = 50）或普通小鼠饲料（n = 50）。在基线和第42、56和70天，通过一种新的经胸超声心动图方法（血管内超声导管）评估左心室射血分数作为心力衰竭的测量指标。从基线到研究结束，COX-2抑制剂治疗小鼠左心室射血分数明显低于对照组（9%对29%，P < 0.01）。COX-2抑制剂处理小鼠的死亡率显著低于对照组（18%对38%，P < 0.01）。这些结果在COX-2抑制剂治疗小鼠（n = 25）和对照组（n = 25）的再验证研究中得到证实。该研究显示，对照小鼠的心脏重量与COX-2抑制剂治疗小鼠的心脏重量大致相同，但显示出更广泛的心肌病迹象（由独立的盲法观察者进行病理分析确定）和更高水平的COX-2蛋白（通过免疫印迹测定[6442 +/- 1635对4300 +/- 2408任意单位，P < 0.022]）。结论：COX-2抑制剂可以减缓阿霉素诱导的心力衰竭小鼠模型的心力衰竭进展。
Background - Progression of heart failure after initial myocardial injury is mediated in part by various redundant inflammatory mediators, including the widely expressed cyclooxygenase-2 (COX-2). Because COX-2 inhibitors are useful in treating many inflammation-mediated diseases, we asked whether COX-2 inhibition can attenuate heart failure progression.Methods and Results - Heart failure was experimentally induced in 100 mice by administration of doxorubicin (4 mg . kg(-1) . wk(-1) for 6 weeks). Beginning at day 42, mice were fed daily with either COX-2 inhibitor - containing mice chow (n = 50) or plain mice chow (controls; n = 50). Left ventricular ejection fraction was evaluated as a measure of heart failure by a novel method of transthoracic echocardiography ( with intravascular ultrasound catheters) at baseline and on days 42, 56, and 70. From baseline to study termination, left ventricular ejection fraction in COX-2 inhibitor - treated mice decreased significantly less than in control mice (9% versus 29%, P < 0.01). Mortality was significantly lower for COX-2 inhibitor - treated mice than for control mice (18% versus 38%, P < 0.01). These results were confirmed in a revalidation study in COX-2 inhibitor - treated mice ( n = 25) and controls ( n = 25). That study revealed that the hearts from control mice weighed roughly the same as hearts from COX-2 inhibitor - treated mice but showed more extensive signs of cardiomyopathy ( as determined by pathological analysis by an independent, blinded observer) and higher levels of COX-2 proteins (as determined by immunoblotting [6442 +/- 1635 versus 4300 +/- 2408 arbitrary units, P < 0.022]).Conclusions - COX-2 inhibitors can attenuate the progression of heart failure in a murine model of doxorubicin-induced heart failure.