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Molecular mechanism of limbs' postischemic revascularization improved by perindopril in diabetic rats / 中华医学杂志(英文版)
Chinese Medical Journal ; (24): 2129-2133, 2008.
Article in English | WPRIM | ID: wpr-350788
ABSTRACT
<p><b>BACKGROUND</b>Currently, there are still divergent opinions about the mechanisms of the impaired neovascularization in diabetic subjects. Due to the remarkable therapeutic effect of angiotensin-converting enzyme inhibititors (ACEIs) on the reduction of blood pressure and the protection of target organs, the clinical application of this kind of drugs is very widespread. However, it is still not clear about the role and related molecular pathway of this kind of drugs in the limbs' postischemic revascularization. It is of major therapeutic importance to resolve these questions. This study aimed to investigate the reasons of the impaired angiogenesis in the hind limbs of rats with diabetic ischemia, the role and related molecular mechanisms of ACEI in postischemic revascularization.</p><p><b>METHODS</b>Hind limbs ischemia was induced in diabetic rats by right femoral artery excision. Diabetic rats were randomly allocated to one of the following treatments for 4 weeks ACEI by perindopril; perindopril in combination with a nitric oxide synthase (NOS) inhibitor; perindopril in combination with bradykinin (BK)-B1 receptor (B1R) antagonist or saline. The differences of angiogenesis, the mRNA and protein expression of endothelial nitric oxide synthase (eNOS), vascular endothelial growth factor (VEGF) and basic fibroblast (bFGF), constitutive nitric oxide synthase (cNOS) activity and nitric oxide (NO) content were observed after treatment.</p><p><b>RESULTS</b>In non-ischemic hind limbs, no significant changes in capillary density, or the mRNA and protein expression of eNOS, VEGF and bFGF, or the NO content and the cNOS activity were observed among all groups. On the contrary, in ischemic hind limbs, the capillary density in diabetic rats decreased by 27% when compared with the control rats, so did the mRNA and protein expression of eNOS, VEGF and bFGF, or the NO content and the cNOS activity (P < 0.05). The capillary density was increased by 1.65-fold in the perindopril treatment group in reference to untreated diabetic rats. Moreover, administration of perindopril enhanced the mRNA expression of eNOS, VEGF, and bFGF by 1.45-, 1.44-, and 1.33-fold, increased the protein content of the above indices by 1.55-, 1.30- and 1.50-fold compared with the untreated diabetic rats respectively. Perindopril also increased NO content and cNOS activity to 1.33- and 1.38-fold of that in untreated diabetic rats. The combination of BK-B1R antagonist significantly decreased the above indices (P < 0.05). In contrast, the combination of NOS inhibitor decreased the expression of eNOS and bFGF, the NO content and the cNOS activity, while the expression of VEGF did not change.</p><p><b>CONCLUSIONS</b>Diabetes mellitus reduces the neovascularization, related growth factors expression and activity in the diabetic rat ischemic legs model. Treatment of perindopril improves postischemic revascularization. This effect is mediated, at least in part, by the BK-B1R-related pathway, and the activation of VEGF/eNOS/bFGF signals may be involved in the pro-angiogenic effect.</p>
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Full text: Available Index: WPRIM (Western Pacific) Main subject: Pharmacology / Blood Glucose / RNA, Messenger / Angiotensin-Converting Enzyme Inhibitors / Fibroblast Growth Factor 2 / Rats, Wistar / Streptozocin / Neovascularization, Physiologic / Perindopril / Vascular Endothelial Growth Factor A Type of study: Prognostic study Limits: Animals Language: English Journal: Chinese Medical Journal Year: 2008 Type: Article

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Full text: Available Index: WPRIM (Western Pacific) Main subject: Pharmacology / Blood Glucose / RNA, Messenger / Angiotensin-Converting Enzyme Inhibitors / Fibroblast Growth Factor 2 / Rats, Wistar / Streptozocin / Neovascularization, Physiologic / Perindopril / Vascular Endothelial Growth Factor A Type of study: Prognostic study Limits: Animals Language: English Journal: Chinese Medical Journal Year: 2008 Type: Article