Pitavastatin treatment normalizes VEGF signaling and cardiac function in STZ‐induced diabetic rat hearts

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 effectiveness of pharmacological intervention on these diabetic defects remains unsettled. Here, we studied the effects of statin (pitavastatin) 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 pitavastatin (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 pitavastatin reversed these alterations to control levels and ameliorated impairment of cardiac function. The present study is the first to show the potential usefulness of a statin in the treatment of cardiac dysfunction in type I diabetes at the molecular level.