Endothelin antagonism normalizes VEGF signaling and cardiac function in STZ-induced diabetic rat hearts
Endothelin antagonism normalizes VEGF signaling and cardiac function in STZ-induced diabetic rat hearts
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DOI：
10.1152/ajpendo.00517.2006
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发表时间：
2007-04-01
影响因子：
5.1
通讯作者：
Miyauchi, Takashi
中科院分区：
文献类型：
--
作者：
Jesmin, Subrina;Zaedi, Sohel;Miyauchi, Takashi
内皮素拮抗剂使STZ诱导的糖尿病大鼠心脏中VEGF信号传导和心脏功能正常化Am J Physiol Endocrinol Metab 292：E1030-E1040，2007.首次发表于2006年12月5日; doi：10.1152/ajpendo.00517.2006。- 最近有报道称，糖尿病患者心脏血管内皮生长因子（VEGF）及其受体表达的异常改变以及冠状动脉侧支循环的发展受损。然而，对糖尿病中这些缺陷的药物干预的存在仍然不确定。在这里，我们研究了内皮素（ET）受体阻滞剂对心脏VEGF信号通路和心脏功能的影响，在Sprague-Dawley大鼠5周后诱导I型糖尿病与链脲佐菌素（65 mg/kg ip）与年龄匹配的对照组大鼠相比。链脲佐菌素（STZ）治疗糖尿病大鼠1周后，给予ET受体拮抗剂SB-209670（1 mg/d）治疗4周。通过Western blot、ELISA、实时PCR和免疫组织化学分析VEGF、其受体及其血管生成信号分子[磷酸化Akt和内皮一氧化氮合酶（eNOS）]，并通过超声心动图评价心功能。采用凝集素和酶双重染色法观察冠状动脉毛细血管形态。我们发现与对照组相比，糖尿病大鼠心脏VEGF及其受体的表达，Akt和eNOS的磷酸化以及冠状动脉毛细血管密度显著降低。用SB-209670治疗糖尿病大鼠将这些改变逆转至对照水平，并改善心脏功能受损。从分子角度来看，本研究是第一个表明ET受体拮抗剂在治疗I型糖尿病心功能不全中的潜在用途。
Endothelin antagonism normalizes VEGF signaling and cardiac function in STZ-induced diabetic rat hearts. Am J Physiol Endocrinol Metab 292: E1030-E1040, 2007. First published December 5, 2006; doi:10.1152/ajpendo.00517.2006. - Abnormal alterations in cardiac expression of vascular endothelial growth factor (VEGF) as well as its receptors and impairment in the development of coronary collaterals have recently been reported in diabetic subjects. However, the presence of pharmacological intervention on these defects in diabetes remains unsettled. Here, we studied the effect of endothelin (ET) receptor blockade on cardiac VEGF signaling pathways and cardiac function in Sprague-Dawley rats 5 wk after induction of type I diabetes with streptozotocin (65 mg/kg ip) in comparison with age-matched control rats. After streptozotocin (1 wk), some diabetic rats were treated with the ET receptor antagonist SB-209670 (1 mg/day) for 4 wk. VEGF, its receptors, and its angiogenic signaling molecules [phosphorylated Akt and endothelial nitric-oxide synthase (eNOS)] were analyzed by Western blot, ELISA, real-time PCR, and immunohistochemistry, and cardiac function was evaluated by echocardiography. Coronary capillary morphology was assessed by lectin and enzymatic double staining. We found significant decreases in cardiac expression of VEGF, its receptors, phosphorylation of Akt and eNOS, and coronary capillary density in diabetic rats compared with controls. Treatment of diabetic rats with SB-209670 reversed these alterations to the control levels and ameliorated impairment of cardiac function. From a molecular point of view, the present study is the first to indicate the potential usefulness of an ET receptor antagonist in the treatment of cardiac dysfunction in type I diabetes.