PARP-1 inhibition alleviates diabetic cardiac complications in experimental animals

被引:27
作者
Zakaria, Esraa M. [1 ]
El-Bassossy, Hany M. [1 ,2 ]
El-Maraghy, Nabila N. [3 ]
Ahmed, Ahmed F. [1 ]
Ali, Abdelmoneim A. [4 ]
机构
[1] Zagazig Univ, Dept Pharmacol, Fac Pharm, Zagazig, Egypt
[2] King Abdulaziz Univ, Dept Pharmacol, Fac Pharm, Jeddah, Saudi Arabia
[3] Future Univ Egypt, Fac Pharmaceut Sci & Pharmaceut Ind, Dept Pharmacol, Cairo, Egypt
[4] Zagazig Univ, Dept Pathol, Fac Vet Med, Zagazig, Egypt
关键词
PARP-1; Type; 2; DM; Diabetic cardiovascular complications; 4-aminobenzamide; Olaparib; POLY(ADP-RIBOSE) POLYMERASE INHIBITION; ENDOTHELIAL-DEPENDENT RELAXATION; ADP-RIBOSE SYNTHETASE; REPERFUSION INJURY; VASCULAR REACTIVITY; HYPERTENSION; RATS; DYSFUNCTION; ACTIVATION; PROTECTS;
D O I
10.1016/j.ejphar.2016.09.008
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Cardiovascular complications are the major causes of mortality among diabetic population. Poly(ADPribose) polymerase-1 enzyme (PARP-1) is activated by oxidative stress leading to cellular damage. We investigated the implication of PARP-1 in diabetic cardiac complications. Type 2 diabetes was induced in rats by high fructose-high fat diet and low streptozotocin dose. PARP inhibitor 4-aminobenzamide (4-AB) was administered daily for ten weeks after diabetes induction. At the end of study, surface ECG, blood pressure and vascular reactivity were studied. PARP-1 activity, reduced glutathione (GSH) and nitrite contents were assessed in heart muscle. Fasting glucose, fructosamine, insulin, and tumor necrosis factor alpha (TNIF-alpha) levels were measured in serum. Finally, histological examination and collagen deposition detection in rat ventricular and aortic sections were carried out. Hearts isolated from diabetic animals showed increased PARP-1 enzyme activity compared to control animals while significantly reduced by 4-AB administration. PARP-1 inhibition by 4-AB alleviated cardiac ischemia in diabetic animals as indicated by ECG changes. PARP-1 inhibition also reduced cardiac inflammation in diabetic animals as evidenced by histopathological changes. In addition, 4 -AB administration improved the elevated blood pressure and the associated exaggerated vascular contractility, endothelial destruction and vascular inflammation seen in diabetic animals. Moreover, PARP-1 inhibition decreased serum levels of TNIF-alpha and cardiac nitrite but increased cardiac GSH contents in diabetic animals. However, PARP-1 inhibition did not significantly affect the developed hyperglycemia. Our findings prove that PARP-1 enzyme plays an important role in diabetic cardiac complications through combining inflammation, oxidative stress, and fibrosis mechanisms. (C) 2016 Published by Elsevier B.V.
引用
收藏
页码:444 / 454
页数:11
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