Direct renin inhibition with aliskiren protects against myocardial ischemia/reperfusion injury by activating nitric oxide synthase signaling in spontaneously hypertensive rats.
Direct renin inhibition with aliskiren protects against myocardial ischemia/reperfusion injury by activating nitric oxide synthase signaling in spontaneously hypertensive rats.
复制标题
阿利吉仑直接抑制肾素可通过激活自发性高血压大鼠的一氧化氮合酶信号来预防心肌缺血/再灌注损伤
DOI：
10.1161/jaha.113.000606
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发表时间：
2014-01-28
影响因子：
5.4
通讯作者：
Ji Y
中科院分区：
文献类型：
--
作者：
Zhang W;Han Y;Meng G;Bai W;Xie L;Lu H;Shao Y;Wei L;Pan S;Zhou S;Chen Q;Ferro A;Ji Y
背景我们验证了阿利吉伦直接抑制血浆局部加压素可以保护自发性高血压大鼠（SHR）免受心肌缺血/再灌注（I/R）损伤的假设，并研究了这种情况发生的机制。方法和结果雄性SHR经口给予生理盐水或阿利吉仑（30或60 mg/kg/d）治疗（4周），并进行30分钟的左前降支冠状动脉闭塞，随后再灌注6或24小时。仅较高剂量显著降低收缩压，较低剂量引起较小的不显著的明显降低。尽管在降低血压作用方面存在差异，但两种剂量均增加了射血分数和缩短分数，并同等地减少了心肌梗死面积。I/R降低了磷脂酰肌醇3激酶（PI 3 K）、磷酸化Akt和磷酸化内皮型一氧化氮合酶（phospho-eNOS）的心脏表达，但增加了诱导型一氧化氮合酶（iNOS）的表达;这些变化均被阿利吉仑消除。此外，阿利吉仑减少了心肌中超氧阴离子的产生，并增加了环鸟苷-3 ′，5 ′-一磷酸，这是一种生物活性一氧化氮的指标。它还降低了I/R后心肌基质金属蛋白酶-2、基质金属蛋白酶-9和金属蛋白酶组织抑制剂-1（TIMP-1）的表达。在Langendorff心脏制备中，阿利吉仑消除了I/R对心脏的不利影响，NOS或PI 3 K抑制消除了这些保护作用。在一项平行研究中，虽然特异性iNOS抑制减少了血浆丙二醛和心肌超氧阴离子的产生，但并不影响I/R对心肌结构和功能的有害影响。结论直接抑制肾素可通过激活PI 3 K-Akt-eNOS通路保护心肌I/R损伤。
Background We tested the hypothesis that direct renin inhibition with aliskiren protects against myocardial ischemia/reperfusion (I/R) injury in spontaneously hypertensive rats (SHR), and examined the mechanism by which this occurs. Methods and Results Male SHR were treated (orally, 4 weeks) with saline or aliskiren (30 or 60 mg kg−1 day−1) and subjected to 30 minutes of left anterior descending coronary artery occlusion followed by 6 or 24 hours of reperfusion. Only the higher dose significantly lowered systolic blood pressure, the lower dose causing a smaller apparent lowering that was nonsignificant. Despite this difference in blood pressure‐lowering effect, both doses increased the ejection fraction and fractional shortening and reduced myocardial infarct size equally. I/R decreased cardiac expression of phosphatidylinositol 3‐kinase (PI3K), phospho‐Akt and phospho‐endothelial nitric oxide synthase (phospho‐eNOS), but increased expression of inducible nitric oxide synthase (iNOS); these changes were all abrogated by aliskiren. Moreover, aliskiren decreased superoxide anion generation and increased cyclic guanosine‐3′,5′‐monophosphate, an index of bioactive nitric oxide, in myocardium. It also decreased the expression of myocardial matrix metalloproteinase‐2, matrix metalloproteinase‐9, and tissue inhibitor of metalloproteinases‐1 (TIMP‐1) following I/R. In a Langendorff heart preparation, the detrimental cardiac effects of I/R were abrogated by aliskiren, and these protective effects were abolished by NOS or PI3K inhibition. In a parallel study, although specific iNOS inhibition reduced plasma malondialdehyde and myocardial superoxide anion generation, it did not affect the deleterious effects of I/R on myocardial structure and function. Conclusions Direct renin inhibition protects against myocardial I/R injury through activation of the PI3K‐Akt‐eNOS pathway.