Moderate cardiac-selective overexpression of angiotensin II type 2 receptor protects cardiac functions from ischaemic injury.
Moderate cardiac-selective overexpression of angiotensin II type 2 receptor protects cardiac functions from ischaemic injury.
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DOI：
10.1113/expphysiol.2011.060673
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发表时间：
2012-01
影响因子：
2.7
通讯作者：
Katovich MJ
中科院分区：
文献类型：
--
作者：
Qi Y;Li H;Shenoy V;Li Q;Wong F;Zhang L;Raizada MK;Sumners C;Katovich MJ
我们假设，血管紧张素2型受体(AT2R)适度的心脏选择性过表达可以保护冠状动脉结扎诱导的心肌梗死(MI)后的心肌免受缺血损伤。在体外实验中，利用Ad-G-AT2R-EGFP在新生大鼠心肌细胞(RNCM)过表达AT2R。实时定量聚合酶链式反应和免疫染色检测AT2R的表达，表明AT2R的有效转导呈剂量依赖关系。AT2R以剂量依赖方式结构性地诱导RNCM细胞凋亡。在体内研究中，将4×1010个rAAV9-CBA-AT2R的载体基因组(VG)注射到5日龄SD大鼠的左心室腔内。6周龄时取心脏，用实时荧光定量聚合酶链式反应和免疫印迹法检测AT2R的表达。与对照组相比表达增加1倍，未检测到细胞凋亡。随后进行了两项体内研究。在一项预防研究中，将4×1010Vg的rAAV9-CBA-AT2R注射到5日龄SD大鼠的左室腔内，并在6周龄时诱发MI。在治疗后的研究中，6周龄动物心梗后即刻在梗死灶周围注射4×1010Vg的rAAV9-CBA-AT2R。在两项活体研究中，在冠状动脉结扎4周后，使用超声心动图和血流动力学测量来评估心脏功能。在活体研究中，心肌梗死大鼠的短轴缩短率和dp/dt显着降低，同时左室舒张末压升高，左室肥厚。在预防研究中，AT2R的适度心脏选择性过表达减轻了上述MI诱导的损伤，也导致了室壁变薄的减少。在治疗后的研究中，AT2R的过度表达部分逆转了MI所致的心功能障碍。MI还可诱导AT1R、ACE和I型胶原mRNA的表达上调，AT2R的过度表达可减弱这些作用。适度的心脏选择性AT2R过表达保护心脏功能免受缺血损伤，这可能至少部分是通过调节心脏RAS的成分和心肌中的胶原水平来实现的。
We hypothesize that moderate cardiac-selective overexpression of the angiotensin type 2 receptor (AT2R) would protect the myocardium from ischemic injury after a myocardial infarction (MI) induced by coronary artery ligation. For the in vitro studies, Ad-G-AT2R-EGFP was used to overexpress AT2R in rat neonatal cardiac myocytes (RNCM). Expression of AT2R, measured by real-time PCR and immunostaining demonstrated efficient transduction of AT2R in a dose-dependent pattern. AT2R constitutively induced apoptosis in RNCM in dose-dependent patterns. For the in vivo studies, 4×1010 vector genome (vg) of rAAV9-CBA-AT2R was injected into the left ventricle chamber of the heart in 5-day-old Sprague-Dawley rats. At six weeks of age, hearts were harvested and expression of AT2R determined by real time PCR and western blotting. Expression was increased one fold over controls and no apoptosis was detected. Two subsequent in vivo studies were performed. In a prevention study 4×1010 vg of rAAV9-CBA-AT2R was injected into the left ventricle chamber of the heart in 5-day-old Sprague-Dawley rats and MI was induced at six week of age. For a post treatment study 4×1010 vg of rAAV9-CBA-AT2R was administrated to the peri-infarcted myocardium area immediately after MI in six week old animals. For both in vivo studies, cardiac functions were assessed using echocardiography and hemodynamic measurements four weeks after coronary artery ligation. In the in vivo studies the MI rats showed significant decreases in fractional shortening and dP/dt with an increased left ventricular end diastolic pressure and a ventricular hypertrophy. For the prevention study, the moderate cardiac-selective overexpression of AT2R attenuated the above MI-induced impairments and also caused a decrease in ventricular wall thinning. In the post treatment study, the overexpression of AT2R partially reversed the MIinduced cardiac dysfunction. MI also induced the up-regulation of AT1R, ACE, and Collagen I mRNA expression, all of which were attenuated by the overexpression of AT2R. Moderate cardiac-selective overexpression of AT2R protects heart function from ischemic injury, which may be mediated, at least in part, through modulation of components of the cardiac RAS and collagen levels in the myocardium.
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DOI：
10.1152/ajpregu.2000.278.3.r781
发表时间：
2000-03-01
影响因子：
2.8
作者：
Ozono, R;Matsumoto, T;Carey, RM
通讯作者：
Carey, RM
影响因子：
37.8
作者：
PFEFFER, MA;BRAUNWALD, E
通讯作者：
BRAUNWALD, E
影响因子：
37.8
作者：
Kaschina, Elena;Grzesiak, Aleksandra;Steckelings, U. Muscha
通讯作者：
Steckelings, U. Muscha
DOI：
10.1152/ajpheart.00957.2003
发表时间：
2005-01-01
影响因子：
4.8
作者：
Nakayama, M;Yan, XH;Lorell, BH
通讯作者：
Lorell, BH
影响因子：
8.3
作者：
Oishi, Y;Ozono, R;Kambe, M
通讯作者：
Kambe, M