Chronic Losartan Treatment Up-Regulates AT1R and Increases the Heart Vulnerability to Acute Onset of Ischemia and Reperfusion Injury in Male Rats.
Chronic Losartan Treatment Up-Regulates AT1R and Increases the Heart Vulnerability to Acute Onset of Ischemia and Reperfusion Injury in Male Rats.
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DOI：
10.1371/journal.pone.0132712
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Zhang L
中科院分区：
文献类型：
--
作者：
Song MA;Dasgupta C;Zhang L
抑制血管紧张素II 1型受体（AT 1 R）是治疗高血压的一种重要疗法，特别是在心肌梗死后即刻。然而，AT 1 R在急性心肌缺血和再灌注损伤中的作用仍然存在争议。因此，本研究确定了慢性氯沙坦治疗对大鼠心脏缺血和再灌注损伤的影响。通过渗透泵对6个月大的雄性大鼠给予氯沙坦（10 mg/kg/天）14天，然后分离心脏，并在Langendorff制备物中进行缺血和再灌注损伤。氯沙坦显著降低平均动脉血压。然而，心脏重量，左心室体重比和基线心功能没有显着改变氯沙坦治疗。有趣的是，长期在体内氯沙坦治疗显著增加缺血诱导的心肌损伤和减少缺血后左心室功能的恢复。这与左心室中AT 1 R和PKCδ表达的显著增加有关。而AT 2 R和PKCε则无明显变化。此外，氯沙坦治疗显著增加了左心室中microRNA（miR）-1、-15b、-92a、-133a、-133b、-210和-499的表达，但降低了miR-21的表达。重要的是，在离体心脏制备物中加入氯沙坦阻断了由体内慢性氯沙坦治疗诱导的缺血损伤增加的作用。结果表明，长期氯沙坦治疗上调AT 1 R/PKCδ并改变心脏中的miR表达模式，导致心脏对缺血和再灌注损伤的脆弱性增加。
Inhibition of angiotensin II type 1 receptor (AT1R) is an important therapy in the management of hypertension, particularly in the immediate post-myocardial infarction period. Yet, the role of AT1R in the acute onset of myocardial ischemia and reperfusion injury still remains controversial. Thus, the present study determined the effects of chronic losartan treatment on heart ischemia and reperfusion injury in rats. Losartan (10 mg/kg/day) was administered to six-month-old male rats via an osmotic pump for 14 days and hearts were then isolated and were subjected to ischemia and reperfusion injury in a Langendorff preparation. Losartan significantly decreased mean arterial blood pressure. However, heart weight, left ventricle to body weight ratio and baseline cardiac function were not significantly altered by the losartan treatment. Of interest, chronic in vivo losartan treatment significantly increased ischemia-induced myocardial injury and decreased post-ischemic recovery of left ventricular function. This was associated with significant increases in AT1R and PKCδ expression in the left ventricle. In contrast, AT2R and PKCε were not altered. Furthermore, losartan treatment significantly increased microRNA (miR)-1, -15b, -92a, -133a, -133b, -210, and -499 expression but decreased miR-21 in the left ventricle. Of importance, addition of losartan to isolated heart preparations blocked the effect of increased ischemic-injury induced by in vivo chronic losartan treatment. The results demonstrate that chronic losartan treatment up-regulates AT1R/PKCδ and alters miR expression patterns in the heart, leading to increased cardiac vulnerability to ischemia and reperfusion injury.