PARP-1 inhibition alleviates diabetic cardiac complications in experimental animals

• Published in: European journal of pharmacology 2016-11, Vol.791, p.444-454
• Main Authors: Zakaria, Esraa M., El-Bassossy, Hany M., El-Maraghy, Nabila N., Ahmed, Ahmed F., Ali, Abdelmoneim A.
• Format: Article
• Language: English
• Subjects: 4-aminobenzamide; Animals; Aorta - drug effects; Aorta - pathology; Aorta - physiopathology; Blood Pressure - drug effects; Coronary Vessels - drug effects; Coronary Vessels - pathology; Coronary Vessels - physiopathology; Diabetes Mellitus, Type 2 - complications; Diabetic cardiovascular complications; Disease Models, Animal; Heart - drug effects; Heart - physiopathology; Heart Conduction System - drug effects; Heart Ventricles - drug effects; Heart Ventricles - pathology; Heart Ventricles - physiopathology; Male; Olaparib; Oxidative Stress - drug effects; PARP-1; Poly (ADP-Ribose) Polymerase-1 - antagonists & inhibitors; Poly (ADP-Ribose) Polymerase-1 - metabolism; Poly(ADP-ribose) Polymerase Inhibitors - pharmacology; Rats; Rats, Sprague-Dawley; Type 2 DM
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2016.09.008

Cardiovascular complications are the major causes of mortality among diabetic population. Poly(ADP-ribose) 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 (TNF-α) 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 TNF-α 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.