Combination renin-angiotensin system blockade and angiotensin-converting enzyme 2 in experimental myocardial infarction: implications for future therapeutic directions
Combination renin-angiotensin system blockade and angiotensin-converting enzyme 2 in experimental myocardial infarction: implications for future therapeutic directions
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DOI：
10.1042/cs20120162
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发表时间：
2012-12-01
期刊：
影响因子：
6
通讯作者：
Burrell, Louise M.
中科院分区：
文献类型：
--
作者：
Burchill, Luke J.;Velkoska, Elena;Burrell, Louise M.
肾素-血管紧张素系统(RAS)在心肌梗死(MI)后被激活，用ACEIs(血管紧张素转换酶抑制剂)或ARBS(血管紧张素受体阻滞剂)阻断RAS可以减缓但不能完全阻止进展为心力衰竭。心肌梗死后心脏血管紧张素转换酶升高，导致血管收缩因子(血管紧张素II)的形成。心肌梗死后血管紧张素转换酶2也被激活，降解血管紧张素转换酶生成血管扩张剂Ang-(1-7)[血管紧张素-(1-7)]。ACE2的过度表达在实验性心肌梗死中提供了心脏保护作用，但关于ACEI和ARB的益处是否通过在MI后增加ACE2来调节，有相互矛盾的证据。在目前的研究中，我们评估了ACEI和ARB单独和联合使用对大鼠心肌梗死模型心脏ACE2的影响。MI大鼠分别给予赋形剂、ACEI(雷米普利1 mg/kg体重)、ARB(Valsartan 10 mg/kg体重)或联合用药(雷米普利1 mg/kg体重和valsartan 10 mg/kg体重)，共28天。假手术大鼠也被研究，只接受交通工具。MI使左心室重量增加(P<；0.0001)，心脏收缩能力受损(P<；0.05)，并激活心脏血管紧张素转换酶2基因(P<；0.05)和蛋白表达(存活心肌，P<；0.05；交界区，P<；0.001；梗死，P<；0.05)。雷米普利和valsartan改善了重塑(P<；0.05)，没有双重治疗的额外效果。虽然雷米普利抑制血管紧张素转换酶，而valsartan阻断血管紧张素受体，但单独或联合治疗都不能增加心脏ACE2的表达。这些结果表明，雷米普利和valsartan的心脏保护作用不是通过上调心脏ACE2来实现的。心肌梗死后增加ACE2的策略可能是对心肌梗死后标准RAS阻断的有益补充。
The RAS (renin-angiotensin system) is activated after MI (myocardial infarction), and RAS blockade with ACEis [ACE (angiotensin-converting enzyme) inhibitors] or ARBs (angiotensin receptor blockers) slows but does not completely prevent progression to heart failure. Cardiac ACE is increased after MI and leads to the formation of the vasoconstrictor AngII (angiotensin II). The enzyme ACE2 is also activated after MI and degrades AngII to generate the vasodilator Ang-(1-7) [angiotensin-(1-7)]. Overexpression of ACE2 offers cardioprotective effects in experimental MI, but there is conflicting evidence as to whether the benefits of ACEis and ARBs are mediated through increasing ACE2 after MI. In the present study, we assessed the effect of an ACEi and ARB, alone and in combination, on cardiac ACE2 in a rat MI model. MI rats received vehicle, ACEi (ramipril; 1 mg/kg of body weight), ARB (valsartan; 10 mg/kg of body weight) or combination (ramipril at 1 mg/kg of body weight and valsartan at 10 mg/kg of body weight) orally for 28 days. Sham-operated rats were also studied and received vehicle alone. MI increased LV (left ventricular) mass (P < 0.0001), impaired cardiac contractility (P < 0.05) and activated cardiac ACE2 with increased gene (P < 0.05) and protein expression (viable myocardium, P < 0.05; border zone, P < 0.001; infarct, P < 0.05). Ramipril and valsartan improved remodelling (P < 0.05), with no additional effect of dual therapy. Although ramipril inhibited ACE, and valsartan blocked the angiotensin receptor, neither treatment alone nor in combination augmented cardiac ACE2 expression. These results suggest that the cardioprotective effects of ramipril and valsartan are not mediated through up-regulation of cardiac ACE2. Strategies that do augment ACE2 after MI may be a useful addition to standard RAS blockade after MI.