Our overall aim is to define the specific role of arginase activity in diabetes-induced cardiovascular disease. These studies will set the stage for developing new strategies to prevent the vascular injury that leads to diabetic heart disease. Endothelial cell (EC) dysfunction is a prominent feature in the vascular complications of diabetes. Our preliminary data show impaired coronary vasorelaxation and perivascular fibrosis/hypertrophy in diabetic rats, which are associated with reactive oxygen species (ROS) formation and increased arginase activity, which diverts L-arg from eNOS to the ornithine pathway. Our data also show that high glucose and ROS increase arginase I expression and that statin HMG CoA reductase inhibitors and supplemental L-citrulline (L-cit) block the actions of diabetes in increasing ROS, inducing arginase expression and activity and causing coronary fibrosis and impaired vasorelaxation. These effects are explained by studies showing that diabetes and high glucose-induced ROS activate the small G protein RhoA, which activates Rho kinase (ROCK). ROCK in turn activates arginase and inhibits eNOS, whereas NO production inhibits the arginase/ornithine pathway and statins enhance eNOS activity, NO formation and inhibit activation of RhoA/ROCK. Additionally, our studies indicate that L-cit, which increases L-arg levels and inhibits arginase activity, maintains L-arg availability for NOS better than L-arg itself. Based on these data, we hypothesize that diabetes and high glucose cause vascular dysfunction by RhoA/ROCK-mediated activation of the arginase/ornithine pathway. Decreased L-arginine availability to eNOS uncouples the enzyme to form superoxide rather than NO which reduces vasodilation. Accelerated activity of the arginase/ornithine pathway induces perivascular fibrosis, hypertrophy, leading to vascular stiffening. This model will be examined using a combination of molecular, pharmacological and biochemical approaches to test the following hypotheses for experiments in diabetic animals, vessels and blood from diabetic patients and cultured cells. 1) Define the molecular mechanisms by which diabetes activates arginase. 2) Test whether diabetes causes impaired EC-dependent vasorelaxation by activating arginase. 3) Test whether diabetes causes vascular fibrosis, hypertrophy and stiffening by activating arginase. 4) Test whether diabetes activates the arginase/ornithine pathway by activation of RhoA/ROCK.

Public Health Relevance

Coronary vascular heart disease which can cause heart attacks is a major health problem, which is much worse in people who have diabetes. Understanding the factors and sequence of events in diabetes which reduce blood flow to heart is critical to preventing and treating this disease. Limiting actions of an enzyme which can prevent the heart from getting enough blood and cause thickening and stiffness of heart blood vessels offers much promise for reducing the incidence of this disease.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Wood, Katherine
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Georgia Regents University
Schools of Medicine
United States
Zip Code
Bhatta, Anil; Sangani, Rajnikumar; Kolhe, Ravindra et al. (2016) Deregulation of arginase induces bone complications in high-fat/high-sucrose diet diabetic mouse model. Mol Cell Endocrinol 422:211-220
Shatanawi, Alia; Lemtalsi, Tahira; Yao, Lin et al. (2015) Angiotensin II limits NO production by upregulating arginase through a p38 MAPK-ATF-2 pathway. Eur J Pharmacol 746:106-14
Bhatta, Anil; Yao, Lin; Toque, Haroldo A et al. (2015) Angiotensin II-induced arterial thickening, fibrosis and stiffening involves elevated arginase function. PLoS One 10:e0121727
Caldwell, Ruth B; Toque, Haroldo A; Narayanan, S Priya et al. (2015) Arginase: an old enzyme with new tricks. Trends Pharmacol Sci 36:395-405
Wang, Lin; Bhatta, Anil; Toque, Haroldo A et al. (2015) Arginase inhibition enhances angiogenesis in endothelial cells exposed to hypoxia. Microvasc Res 98:1-8
Narayanan, S P; Xu, Z; Putluri, N et al. (2014) Arginase 2 deficiency reduces hyperoxia-mediated retinal neurodegeneration through the regulation of polyamine metabolism. Cell Death Dis 5:e1075
Toque, Haroldo A; Nunes, Kenia P; Rojas, Modesto et al. (2013) Arginase 1 mediates increased blood pressure and contributes to vascular endothelial dysfunction in deoxycorticosterone acetate-salt hypertension. Front Immunol 4:219
Liu, Hua; Zhang, Wenbo; Xu, Zhimin et al. (2013) Hyperoxia causes regression of vitreous neovascularization by downregulating VEGF/VEGFR2 pathway. Invest Ophthalmol Vis Sci 54:918-31
Yao, Lin; Chandra, Surabhi; Toque, Haroldo A et al. (2013) Prevention of diabetes-induced arginase activation and vascular dysfunction by Rho kinase (ROCK) knockout. Cardiovasc Res 97:509-19
Patel, Chintan; Rojas, Modesto; Narayanan, S Priya et al. (2013) Arginase as a mediator of diabetic retinopathy. Front Immunol 4:173

Showing the most recent 10 out of 43 publications