Research in Focus: Diabetes and Cardiovascular Disease Research

Issue One: September 2013

RESEARCH IN

FOCUS Diabetes and Cardiovascular Disease Research Dr. Brian Rodrigues and Dr. Kath MacLeod

Introduction Diabetes and Cardiovascular Disease Research The incidence of diabetes has reached epidemic proportions. Cardiovascular disease is a substantial driver of health care costs among people with diabetes, in addition to being the leading cause of diabetes-related death. Although atherosclerotic vascular disease is a primary reason for this cardiovascular dysfunction, patients with diabetes are also more likely to be hypertensive, have worse outcomes following heart attacks and suffer from heart failure. The latter is an outcome of an intrinsic malfunction of the heart muscle. At the Faculty of Pharmaceutical Sciences, Dr. Kath MacLeod and Dr. Brian Rodrigues are examining the mechanisms behind the cardiac and vascular dysfunction seen during diabetes, in an effort to prevent or delay these changes.

The Dr. Brian Rodrigues Lab Lab Members Ying Wang, PhD student Dahai Zhang, PhD student Amy Chiu, PhD student Fulong Wang, PhD student Nathaniel Lal, MSc student Bahira Hussein, Research technician Andrea Wan, Undergraduate research assistant Research Summary After diabetes and the development of hyperglycemia, there is an increased translocation of LPL from the cardiomyocyte cell surface to the apical side of endothelial cells. This process is dependent on the ability of high glucose to rapidly release active heparanase from the endothelial cell into the interstitial space to splice cardiomyocyte HSPG, and release 2 路 RESEARCH IN FOCUS

bound LPL. Cardiomyocyte cell surface VEGF is also liberated by heparanase, but principally by latent heparanase. This cytokine could be a significant contributor towards enabling fatty acid delivery and utilization in cardiomyocytes through its activation of AMPK. Gaining more insight into the heparanase-LPL-VEGF axis may assist in devising novel therapeutic strategies to restore metabolic equilibrium, curb lipotoxicity, and help prevent or delay heart dysfunction seen during diabetes.

Schematic

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Relevant Publications Wang, Y., Zhang, D., Pei-Ling Chiu, A., Wan, A., Neumaier, K., Vlodavsky, I., and Rodrigues, B. Endothelial heparanase regulates heart metabolism by stimulating lipoprotein lipase secretion from cardiomyocytes. Arterioscler.

Thromb. Vasc. Biol. 33:894-902, 2013.

Wang, F., Wang, Y., Zhang, D., Puthanveetil, P., Johnson, J. D., Abrahani, A., and Rodrigues, B. Fatty acid-induced nuclear translocation of heparanase uncouples glucose metabolism in endothelial cells. Arterioscler. Thromb.

Vasc. Biol. 32: 406-414, 2012.

Wang, Y., Puthanveetil, P., Wang. F., Kim, M. S., Abrahani, A., and Rodrigues, B. The severity of diabetes governs vascular LPL by affecting enzyme dimerization and disassembly. Diabetes 60:2041-2050, 2011.

The Dr. Kath MacLeod Lab Lab Members Dr. Guorong Lin, Research Associate Dr. Hesham Soliman, Postdoctoral Fellow Vongai Nyamandi, PhD Student Marysol Garcia Patino, PhD student Julia Varela, PhD student Research Summary In diabetes, hyperglycemia leads to activation of the RhoA/ROCK pathway, PKCß2 and inducible nitric oxide synthase (iNOS) in cardiomyocytes and vascular smooth muscle cells, all of which have been implicated in cardiovascular dysfunction. Our research has shown that their activation in cardiomyocytes is sustained by a positive feedback loop that requires an intact actin cytoskeleton for its operation, and that leads to increased oxidative stress and impaired regulation of intracellular Ca2+ levels.

Understanding the molecular mechanisms by which activation of the loop leads to increased oxidative stress and impaired calcium homeostasis 4 · RESEARCH IN FOCUS

may lead to identification of novel targets for the treatment of diabetic cardiomyopathy and vascular dysfunction.

Schematic Diabetes

ROCK PKCβ2

RhoA

F-actin iNOS

Ca2+ dysregulation

ROS

Cell damage Relevant Publications Rao, M, Soliman, H, Bankar, G, Lin, G and MacLeod, KM. (2013). Contribution of Rho kinase to blood pressure regulation and vasoconstrictor responsiveness in type 2 diabetic Goto-Kakazaki rats. J. Hypertension 31:1160-9 Soliman, H, Gador, A, Lu, S, Lin, G and MacLeod, KM. (2012). Diabetesinduced increased oxidative stress in cardiomyocytes is sustained by a positive feedback loop involving Rho kinase and PKCß2. Am. J. Physiol. Heart Circ.

Physiol. 303:H989-H1000.

Nagareddy, PR, Soliman, H, Lin, G, Rajput, PS, Kumar, U, McNeill, JH and MacLeod, KM. (2009). Selective inhibition of protein kinase Cß2 attenuates inducible nitric oxide synthase-mediated cardiovascular abnormalities in streptozotocin-diabetic rats.

Diabetes 58: 2355-64.

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