PARP-1 Inhibition Attenuates Oxidative Stress and Hypertension in Diabetic Mice - The 65th Annual Conference of the Israel Heart Society & The Israel Society of Cardiothoracic Surgery, 24-25 April 2018

maayan Waldman Felsenstein Research Center. Rabin Medical Center, Sackler School of Medicine, Tel Aviv University, Petach Tiqwa, Israel Leviev Heart Center, Sheba Medical Center and Sackler School of Medicine, Tel Aviv University, Ramat Gan, Israel Vadim Nudelman Felsenstein Research Center. Rabin Medical Center, Sackler School of Medicine, Tel Aviv University, Petach Tiqwa, Israel Asher Shainberg Life Sciences, Bar Ilan University, Ramat Gan, Israel Nader G. Abraham Department of Pharmacology, New York Medical College, Valhalla, New York, USA Dan Aravot Felsenstein Research Center. Rabin Medical Center, Sackler School of Medicine, Tel Aviv University, Petach Tiqwa, Israel Michael Arad Leviev Heart Center, Sheba Medical Center and Sackler School of Medicine, Tel Aviv University, Ramat Gan, Israel Edith Hochhauser Felsenstein Research Center. Rabin Medical Center, Sackler School of Medicine, Tel Aviv University, Petach Tiqwa, Israel

Background: Diabetes mellitus (DM) often follows impaired glucose tolerance in obesity and is frequently associated with other comorbidities, e.g. hypertension which is an independent cause of myocardial remodeling and increases the risk of heart failure.

The DNA bound protein PARP (poly ADP ribose) polymerase catalyses a post translational modification (polymerization of negatively charged ADP-ribose chains) of nuclear proteins. PARP-1 activation is NAD⁺ dependent and takes part in DNA repair and in chromatin remodeling and has a function in transcriptional regulation, telomere cohesion and cell division, intracellular trafficking and energy metabolism.

Aim: We examined the protective properties of PARP-1 inhibition by INO1001 on heart weight, blood pressure (BP), glucose levels and hypertrophy.

Methods: Leptin resistant (db/db) mice suffer from obesity and DM. To enhance development of cardiomyopathy, angiotensin II (AT) was administered for 4 weeks to 14-16 week old mice with ALZET osmotic pump. Mice were concomitantly treated with INO (5mg/kg/day) (n=5-6/group).

Results: Only AT treated db/db mice developed cardiomyopathy. Animals were obese, and had elevated serum glucose and oxidative stress marker (MDA). Hearts developed left ventricular hypertrophy; leukocytes infiltration and fibrosis on histology. PARP-1 inhibition in the diabetic mice reduced blood pressure (p=0.0001) and blood glucose (p=0.007). The increase in heart weight in the diabetic mice was attenuated (p=0.002) as well as cardiac fibrosis. Oxidative stress (MDA levels) where elevated in the diabetic mice and were reduced in INO1001 treated animals (p<0.05).

Inhibition of PARP-1 in cardiomyocytes, exposed to high concentration of glucose with or without AT (in-vitro) led to a marked reduction of cellular ROS (p<0.01).

Conclusion: PARP1 inhibitor INO1001 attenuated hypertension, cardiac fibrosis, hypertrophy and oxidative stress in diabetic mice.The results of this study reveal the role of PARP-1 in diabetic heart disease and the potential role of its inhibition in treatment of diabetic cardiomyopathy