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

Subrina Jesmin, Sohel Zaedi, Nobutake Shimojo, Motoyuki Iemitsu, Koichi Masuzawa, Naoto Yamaguchi, Chishimba N. Mowa, Seiji Maeda, Yuichi Hattori, Takashi Miyauchi

Research output: Contribution to journalArticlepeer-review

41 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)E1030-E1040
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Volume292
Issue number4
DOIs
Publication statusPublished - 2007 Apr
Externally publishedYes

Keywords

  • Akt
  • Diabetes mellitus
  • Echocardiography
  • Endothelial nitric oxide synthase
  • Streptozotocin
  • Vascular endothelial growth factor

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Physiology
  • Physiology (medical)

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