Angiotensin type 1a receptor-deficient mice develop diabetes-induced cardiac dysfunction, which is prevented by renin-angiotensin system inhibitors.
Angiotensin type 1a receptor-deficient mice develop diabetes-induced cardiac dysfunction, which is prevented by renin-angiotensin system inhibitors.
复制标题
DOI：
10.1186/1475-2840-12-169
复制
发表时间：
2013-11-12
影响因子：
9.3
通讯作者：
Kumar R
中科院分区：
文献类型：
--
作者：
Yong QC;Thomas CM;Seqqat R;Chandel N;Baker KM;Kumar R
糖尿病引起的器官损害与肾素-血管紧张素系统（RAS）的激活显著相关。最近，几项研究已经证明了RAS从细胞外系统到细胞内系统的变化，在几种细胞类型中，响应于高环境葡萄糖水平。在心肌细胞中，细胞内血管紧张素（ANG）II的合成和作用分别不依赖于ACE和AT 1。然而，该系统在糖尿病诱导的器官损伤中的作用尚不清楚。为了确定细胞内ANG II在糖尿病性心肌病中的作用，我们在AT 1a受体缺陷（AT 1a-KO）小鼠中使用链脲佐菌素诱导糖尿病，以排除细胞外ANG II的任何影响。此外，用肾素抑制剂阿利吉仑、ACE抑制剂苯那普利拉和AT 1受体阻断剂缬沙坦治疗糖尿病动物。AT 1a-KO小鼠在糖尿病10周后出现显著的舒张和收缩功能障碍，如超声心动图所示。所有三种药物都防止了这些动物心脏功能障碍的发展，而不影响血压或葡萄糖水平。在糖尿病动物中观察到激肽释放酶-激肽系统（KKS）组分的显著下调，这在很大程度上被苯那普利拉和缬沙坦阻止，而阿利吉仑使激肽原表达正常化。这些数据表明，AT 1a受体，因此细胞外ANG II，糖尿病心肌病的发展是不需要的。KKS可能有助于苯那普利拉和缬沙坦对糖尿病心肌病的有益作用。阿利吉仑的抑制作用表明细胞内ANG II的作用，这需要在未来的研究中确认。
Diabetes-induced organ damage is significantly associated with the activation of the renin-angiotensin system (RAS). Recently, several studies have demonstrated a change in the RAS from an extracellular to an intracellular system, in several cell types, in response to high ambient glucose levels. In cardiac myocytes, intracellular angiotensin (ANG) II synthesis and actions are ACE and AT1 independent, respectively. However, a role of this system in diabetes-induced organ damage is not clear. To determine a role of the intracellular ANG II in diabetic cardiomyopathy, we induced diabetes using streptozotocin in AT1a receptor deficient (AT1a-KO) mice to exclude any effects of extracellular ANG II. Further, diabetic animals were treated with a renin inhibitor aliskiren, an ACE inhibitor benazeprilat, and an AT1 receptor blocker valsartan. AT1a-KO mice developed significant diastolic and systolic dysfunction following 10 wks of diabetes, as determined by echocardiography. All three drugs prevented the development of cardiac dysfunction in these animals, without affecting blood pressure or glucose levels. A significant down regulation of components of the kallikrein-kinin system (KKS) was observed in diabetic animals, which was largely prevented by benazeprilat and valsartan, while aliskiren normalized kininogen expression. These data indicated that the AT1a receptor, thus extracellular ANG II, are not required for the development of diabetic cardiomyopathy. The KKS might contribute to the beneficial effects of benazeprilat and valsartan in diabetic cardiomyopathy. A role of intracellular ANG II is suggested by the inhibitory effects of aliskiren, which needs confirmation in future studies.
登录
查看更多内容
DOI：
10.1111/j.1440-1681.2011.05486.x
发表时间：
2011-04
影响因子：
2.9
作者：
Huang J;Matavelli LC;Siragy HM
通讯作者：
Siragy HM
影响因子：
8.3
作者：
Kurisu, S;Ozono, R;Matsubara, H
通讯作者：
Matsubara, H
DOI：
10.1152/ajprenal.00501.2007
发表时间：
2008-05-01
影响因子：
4.2
作者：
Buleon, Marie;Allard, Julien;Tack, Ivan
通讯作者：
Tack, Ivan
DOI：
10.1124/jpet.107.124859
发表时间：
2007-10-01
影响因子：
3.5
作者：
Messadi-Laribi, Erij;Griol-Charhbili, Violaine;Richer, Christine
通讯作者：
Richer, Christine
影响因子：
5.5
作者：
Baker, Kenneth M.;Kumar, Rajesh
通讯作者：
Kumar, Rajesh