Direct renin inhibition prevents cardiac dysfunction in a diabetic mouse model: comparison with an angiotensin receptor antagonist and angiotensin-converting enzyme inhibitor.
Direct renin inhibition prevents cardiac dysfunction in a diabetic mouse model: comparison with an angiotensin receptor antagonist and angiotensin-converting enzyme inhibitor.
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DOI：
10.1042/cs20120448
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发表时间：
2013-04
期刊：
影响因子：
--
通讯作者：
Kumar R
中科院分区：
文献类型：
--
作者：
Thomas CM;Yong QC;Seqqat R;Chandel N;Feldman DL;Baker KM;Kumar R
高血压可上调心肌细胞内血管紧张素II的产生，其作用可被肾素抑制剂比血管紧张素受体阻滞剂（ARB）或ACE抑制剂更有效地阻断。在此，我们确定了肾素抑制剂是否比ARB或ACE抑制剂更有效地预防糖尿病性心肌病。用链脲佐菌素诱导成年小鼠糖尿病10周。糖尿病小鼠通过皮下微型泵接受胰岛素、阿利吉仑（肾素抑制剂）、苯那普利拉（ACE抑制剂）或缬沙坦（ARB）治疗。在糖尿病小鼠中观察到舒张和收缩心脏功能的显著损害，这完全被所有三种RAS抑制剂所阻止。高血压显著增加心脏氧化应激和循环炎性细胞因子，阿利吉仑和贝那普利拉阻断，而缬沙坦部分有效。糖尿病增加心脏（原）肾素受体（PRR）的表达和早幼粒细胞锌指蛋白（PLZF）的核转位，这是完全阻止阿利吉仑和缬沙坦，和部分贝那普利拉。肾素抑制剂对心脏功能的保护作用与ARB和ACE抑制剂相似。PRR激活PLZF代表了糖尿病心肌病的一种新机制。这三种药物对氧化应激、细胞因子和PRR表达的不同影响表明其作用机制存在细微差异。
Hyperglycemia upregulates intracellular angiotensin II production in cardiac myocytes, effects of which are blocked more effectively by renin inhibition than angiotensin receptor blockers (ARBs) or ACE inhibitors. Here we determined whether renin inhibition is more effective at preventing diabetic cardiomyopathy than an ARB or ACE inhibitor. Diabetes was induced in adult mice for 10 wks by streptozotocin. Diabetic mice were treated with insulin, aliskiren (renin inhibitor), benazeprilat (ACE inhibitor), or valsartan (ARB) via subcutaneous minipumps. Significant impairment in diastolic and systolic cardiac function was observed in diabetic mice, which was completely prevented by all three RAS inhibitors. Hyperglycemia significantly increased cardiac oxidative stress and circulating inflammatory cytokines, which were blocked by aliskiren and benazeprilat, while valsartan was partially effective. Diabetes increased cardiac (pro)renin receptor (PRR) expression and nuclear translocation of promyelocytic zinc finger protein (PLZF), which was completely prevented by aliskiren and valsartan, and partially by benazeprilat. Renin inhibition provided similar protection of cardiac function as ARBs and ACE inhibitors. Activation of PLZF by PRR represented a novel mechanism in diabetic cardiomyopathy. Differential effects of the three agents on oxidative stress, cytokines, and PRR expression suggested subtle differences in their mechanism of action.