Heart angiotensin II-induced cardiomyocyte hypertrophy suppresses coronary angiogenesis and progresses diabetic cardiomyopathy
Heart angiotensin II-induced cardiomyocyte hypertrophy suppresses coronary angiogenesis and progresses diabetic cardiomyopathy
复制标题
DOI：
10.1152/ajpheart.00663.2011
复制
发表时间：
2012-05-01
影响因子：
4.8
通讯作者：
Kusano, Eiji
中科院分区：
文献类型：
--
作者：
Masuda, Takahiro;Muto, Shigeaki;Kusano, Eiji
增田T，武藤S，藤泽G，岩津Y，木村M，小林T，Nonaka-Sarukawa M，Sasaki N，渡边Y，Shinohara M，村上T，岛田K，小林E，草野E.心脏血管紧张素II诱导的心肌细胞肥大抑制冠状动脉血管生成并进展为糖尿病心肌病。Am J Physiol Heart Circ Physiol 302：H1871-H1883，2012.首次发表于2012年3月2日; doi：10.1152/ajpheart.00663.2011。为了研究心脏血管紧张素II是否以及如何影响心肌细胞肥大和冠状动脉血管生成之间的协调，并有助于糖尿病心肌病的发病机制，我们使用了无和有奥美沙坦酯（血管紧张素II受体阻滞剂）治疗的自发性糖尿病托里（SDT）大鼠。在SDT大鼠，左心室（LV）ANG II，但不循环ANG II，增加在8和16周后糖尿病发作。SDT大鼠在8周时出现左室肥厚和舒张功能障碍，随后在16周时出现左室收缩功能障碍，无高血压。SDT大鼠左心室表现出心肌细胞肥大和缺氧诱导因子-1 α表达增加，在8周和16周更大程度上，仅在16周出现间质纤维化。在SDT大鼠中，冠状动脉血管生成增加，增强毛细血管增殖和血管生成因子VEGF的上调，在8周，但减少VEGF增强毛细血管凋亡和抑制毛细血管增殖，尽管在16周的VEGF的上调。在SDT大鼠中，VEGF受体-2的磷酸化水平在8周时增加，而抗血管生成因子血小板反应蛋白-1的表达在16周时增加。除高血糖症或血压外，所有这些事件均被奥美沙坦酯逆转。这些结果表明，左心室血管紧张素II在SDT大鼠在8和16周诱导心肌细胞肥大，而不影响高血糖症或血压，促进和抑制冠状动脉血管生成，分别通过VEGF和血小板反应蛋白-1产生的肥大心肌细胞在慢性缺氧。血小板反应蛋白-1可能在糖尿病心肌病的进展中发挥重要作用。
Masuda T, Muto S, Fujisawa G, Iwazu Y, Kimura M, Kobayashi T, Nonaka-Sarukawa M, Sasaki N, Watanabe Y, Shinohara M, Murakami T, Shimada K, Kobayashi E, Kusano E. Heart angiotensin II-induced cardiomyocyte hypertrophy suppresses coronary angiogenesis and progresses diabetic cardiomyopathy. Am J Physiol Heart Circ Physiol 302: H1871-H1883, 2012. First published March 2, 2012; doi:10.1152/ajpheart.00663.2011.-To examine whether and how heart ANG II influences the coordination between cardiomyocyte hypertrophy and coronary angiogenesis and contributes to the pathogenesis of diabetic cardiomyopathy, we used Spontaneously Diabetic Torii (SDT) rats treated without and with olmesartan medoxomil (an ANG II receptor blocker). In SDT rats, left ventricular (LV) ANG II, but not circulating ANG II, increased at 8 and 16 wk after diabetes onset. SDT rats developed LV hypertrophy and diastolic dysfunction at 8 wk, followed by LV systolic dysfunction at 16 wk, without hypertension. The SDT rat LV exhibited cardiomyocyte hypertrophy and increased hypoxia-inducible factor-1 alpha expression at 8 wk and to a greater degree at 16 wk and interstitial fibrosis at 16 wk only. In SDT rats, coronary angiogenesis increased with enhanced capillary proliferation and upregulation of the angiogenic factor VEGF at 8 wk but decreased VEGF with enhanced capillary apoptosis and suppressed capillary proliferation despite the upregulation of VEGF at 16 wk. In SDT rats, the phosphorylation of VEGF receptor-2 increased at 8 wk alone, whereas the expression of the antiangiogenic factor thrombospondin-1 increased at 16 wk alone. All these events, except for hyperglycemia or blood pressure, were reversed by olmesartan medoxomil. These results suggest that LV ANG II in SDT rats at 8 and 16 wk induces cardiomyocyte hypertrophy without affecting hyperglycemia or blood pressure, which promotes and suppresses coronary angiogenesis, respectively, via VEGF and thrombospondin-1 produced from hypertrophied cardiomyocytes under chronic hypoxia. Thrombospondin-1 may play an important role in the progression of diabetic cardiomyopathy in this model.