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This Article Full Text Full Text (PDF) All Versions of this Article: 292/4/E1030    most recent 00517.2006v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (3) Citing Articles via Google Scholar Google Scholar Articles by Jesmin, S. Articles by Miyauchi, T. Search for Related Content PubMed PubMed Citation Articles by Jesmin, S. Articles by Miyauchi, T.

Endothelin antagonism normalizes VEGF signaling and cardiac function in STZ-induced diabetic rat hearts

¹Center for Tsukuba Advanced Research Alliance, University of Tsukuba, Tsukuba; ²Department of Pharmacology, School of Medicine, University of Toyama, Toyama, Japan; and ³Department of Biology, Appalachian State University, Boone, North Carolina

Submitted 25 September 2006 ; accepted in final form 28 November 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.

diabetes mellitus; echocardiography; endothelial nitric oxide synthase; Akt; vascular endothelial growth factor; streptozotocin

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