HO-1 Mediates the Cardioprotective Effect of Caloric Restriction in Diabetic Angiotensin Induced Cardiomyopathy - The 66th Annual Conference of the Israel Heart Society & The Israel Society of Cardiothoracic Surgery

maayan Waldman ^1,2 Vadim Nudelman ¹ Asher Shainberg ³ Romi Zemel ¹ Ran Kornwoski ¹ Dan Aravot ¹ Nader G Abraham ⁴ Michael Arad ² Edith Hochhauser ¹

¹Cardiac Research Laboratory, Felsenstein Medical Research Institute, Sackler Faculty of Medicine, Tel Aviv University, Israel
²Levaiev Heart Center, Sheba Medical Center, Tel Hashomer and Sackler School of Medicine, Tel Aviv University
³Faculty of Life Sciences, Bar Ilan University
⁴Department of Pharmacology, New York Medical College

Diabetes mellitus type 2 (DM2) leads to cardiomyopathy characterized by cardiomyocyte hypertrophy, followed by mitochondrial dysfunction and fibrosis, all of which are aggravated by angiotensin II (AT). SIRT 1 and its targets transcriptional coactivator PGC-1α (Peroxisome proliferator-activated receptor-γ coactivator) and Heme Oxygenase-1 (HO-1) axis modulate mitochondrial biogenesis and oxidative metabolism. We have shown the beneficial effect of caloric restriction (CR) on cardiomyopathy in diabetic mice through intracellular signaling pathways involving SIRT-PGC-1α axis^1,2. In the current study we examined the role of HO-1 in cardiomyopathy in diabetes.

Methods: Obese Leptin resistant (db/db) mice suffering from DM2 were treated with AT for 4 weeks to enhance the development of cardiomyopathy^1,2. Mice were concomitantly treated with either CR (65% of calories) with or without the HO-1 inhibitor SnMP (Tin mesoporphyrin) or fed ad libitum. Cardiomyocytes were exposed to different levels of glucose (7.5-33 mM), treated with SnMP or the HO-1 inducer CoPP (Cobalt Protoporphyrin).

Results: CR attenuated cardiac hypertrophy and in AT treated DM2 mice. Diabetic cardiomyopathy was demonstrated by reduced cardiac function and elevated Troponin T, together with decreased HO-1 levels and elevated levels of the oxidative marker malondialdehyde (MDA). Administration of HO-1 inhibitor SnMP concomitantly with CR abolished the beneficial effect on cardiac hypertrophy and on metabolic dysfunction markers represented by Adiponectin, SIRT 1, PPARγ, PGC-1α and MDA. Mitochndrial ROS levels were significantly increased in high glucose cardiomyocytes cell culture. Inhibition of HO-1 activity in cardiomyocytes with SnMP led to a marked reduction in both SIRT1 and PGC-1α. HO-1 activator CoPP increased the levels of SIRT1, PGC-1α and HO-1 and attenuated the myocardial ROS activity.

Conclusion: These results suggest a causal relationship between SIRT1, PGC-1α and HO-1 signaling and attenuation of diabetic cardiomyopathy through reduction of mitochondrial dysfunction and ROS production.

1Exp Cell Res 350 (2016)

2Cardiovasc Diabetol 17 (2018)