Hyperhomocysteinemia and hypercholesterolemia are common cardiovascular risk factors that often occur together in patients with vascular thrombotic events. A better understanding of the pathophysiological pathways by which hyperhomocysteinemia and hypercholesterolemia, alone or in combination, predispose to vascular dysfunction is needed to develop more selective targets for the prevention and treatment of vascular events. During the previous funding period, this project investigated mechanisms of vascular dysfunction in murine models of hyperhomocysteinemia. We now propose to focus on interactions between hyperhomocysteinemia and hypercholesterolemia that lead to vascular dysfunction, neointima formation, and thrombosis. Our preliminary data suggest that hyperhomocysteinemia and hypercholesterolemia induce cellular stress responses (oxidative stress and endoplasmic reticulum (ER) stress) through common mechanisms, including the activation of NADPH oxidase and T cell death-associated gene 51 (TDAG51). The overall goal of this project is to define the molecular mechanisms by which hyperhomocysteinemia and hypercholesterolemia, alone or in combination, lead to vascular dysfunction and thrombosis. Our specific objectives are to determine the mechanistic roles of NADPH oxidase, which we hypothesize to be a major source of oxidative stress, and TDAG51, which we hypothesize to be a major mediator of ER stress. We will use genetically altered mice to probe mechanisms that lead to, and protect against vasomotor dysfunction, neointima formation, and thrombosis induced by hyperhomocysteinemia and/or hypercholesterolemia.
In Aim 1, we will test the hypothesis that hyperhomocysteinemia and hypercholesterolemia induce cellular oxidative stress, vascular dysfunction, increased neointima formation, and enhanced susceptibility to thrombosis through a mechanism involving vascular NADPH oxidase. We propose to test this hypothesis by determining the vascular phenotypic effects of altered expression of the NADPH catalytic subunits Nox1 and Nox4, as well as peroxisome proliferator-activated receptor gamma (PPAR3), in vascular smooth muscle cells (SMC) and mice.
In Aim 2, we will test the hypothesis that hyperhomocysteinemia and hypercholesterolemia induce ER stress, leading to TDAG51-mediated vasomotor dysfunction, increased neointimal formation, and enhanced susceptibility to thrombosis. We propose to test this hypothesis by determining the vascular phenotypic effects of altered expression of TDAG51 and glucose-regulated protein 78 (GRP78;an ER chaperone that protects from ER stress) in endothelial cells (EC), SMC, and mice. We also propose to ascertain the role of PPAR3 downregulation in mediating the vascular effects of ER stress and TDAG51 by determining the vascular phenotypic effects of tissue-specific overexpression of dominant-negative PPAR3 in endothelium or vascular muscle. Thus, we propose to use these models and approaches to define the roles of two fundamental cellular stress pathways, each of which has the potential to be targeted therapeutically.
Cardiovascular disease and its complications are major causes of death, morbidity, and health care expenditures. Hyperhomocysteinemia and hypercholesterolemia are common cardiovascular risk factors that often occur together in patients with clinical vascular events. The goals of this project are to define the molecular mechanisms by which hyperhomocysteinemia and hypercholesterolemia, alone or in combination, lead to adverse vascular events, and to identify new targets for therapy.
|Jin, Hong; Gebska, Milena A; Blokhin, Ilya O et al. (2015) Endothelial PPAR-? protects against vascular thrombosis by downregulating P-selectin expression. Arterioscler Thromb Vasc Biol 35:838-44|
|Klutho, Paula J; Pennington, Steven M; Scott, Jason A et al. (2015) Deletion of Methionine Sulfoxide Reductase A Does Not Affect Atherothrombosis but Promotes Neointimal Hyperplasia and Extracellular Signal-Regulated Kinase 1/2 Signaling. Arterioscler Thromb Vasc Biol 35:2594-604|
|Dayal, Sanjana; Gu, Sean X; Hutchins, Ryan D et al. (2015) Deficiency of superoxide dismutase impairs protein C activation and enhances susceptibility to experimental thrombosis. Arterioscler Thromb Vasc Biol 35:1798-804|
|Gu, Sean X; Stevens, Jeff W; Lentz, Steven R (2015) Regulation of thrombosis and vascular function by protein methionine oxidation. Blood 125:3851-9|
|Rodionov, Roman N; Jarzebska, Natalia; Weiss, Norbert et al. (2014) AGXT2: a promiscuous aminotransferase. Trends Pharmacol Sci 35:575-82|
|Dayal, Sanjana; Blokhin, Ilya O; Erger, Rochelle A et al. (2014) Protective vascular and cardiac effects of inducible nitric oxide synthase in mice with hyperhomocysteinemia. PLoS One 9:e107734|
|Pelham, Christopher J; Keen, Henry L; Lentz, Steven R et al. (2013) Dominant negative PPAR? promotes atherosclerosis, vascular dysfunction, and hypertension through distinct effects in endothelium and vascular muscle. Am J Physiol Regul Integr Comp Physiol 304:R690-701|
|Blokhin, Ilya O; Lentz, Steven R (2013) Mechanisms of thrombosis in obesity. Curr Opin Hematol 20:437-44|
|Klykov, Corinne M; Lentz, Steven R (2013) Trends in clinical laboratory homocysteine testing from 1997 to 2010: the impact of evidence on clinical practice at a single institution. Clin Chem Lab Med 51:671-5|
|Dayal, Sanjana; Wilson, Katina M; Motto, David G et al. (2013) Hydrogen peroxide promotes aging-related platelet hyperactivation and thrombosis. Circulation 127:1308-16|
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