It has been well documented that cardiovascular complications of diabetes account for 75% of all deaths in patients with type 2 diabetes. Hypertension occurs approximately twice as frequently in patients with diabetes compared with non-diabetic individuals. Although it is clear that the state of diabetes confers an increased risk of cardiovascular events, the mechanism by which metabolic perturbations influence vascular function and structure remain to be further defined. Emerging data suggest that peroxisome proliferator-activated receptor-? (PPAR?) and angiotensin II (Ang II) type 1 receptor (AT1R) are two critical determinants that may provide functional links between obesity/diabetes, hypertension and cardiovascular disease (CVD). Recently, we have reported the identification of nitroalkene derivatives of linoleic acid (LNO2) and oleic acid (OA-NO2) with concentrations exceeding 1 ?M in the human circulation, as potent endogenous PPAR-gamma ligands. Intriguingly, our preliminary studies have demonstrated for the first time that nitroalkenes not only can block Ang II binding to AT1R, but also suppress the AT1R expression in vascular smooth muscle cells (VSMC). In addition, we have observed that exogenous administration of OA-NO2 decreases blood pressure in mice. Therefore, nitroalkenes may exert ?vascular and metabolic protective? effects through a combination of down- regulation of the AT1R signaling pathway and activation of PPAR?-dependent protective events in VSMC. In this proposal, we will test the central hypothesis that nitroalkenes are novel endogenous molecules that regulate blood pressure and hypertensive vascular remodeling by activating antihypertensive and antidiabetic signaling pathways in VSMC. Specifically, we will: 1). Determine the molecular mechanisms of OA-NO2-inhibition of the AT1R signaling pathway;2). Define the contributory roles of OA-NO2-mediated AT1R and PPAR? signaling pathways in the regulation of VSMC proliferation;3). Define the contributory roles of OA-NO2- mediated AT1R and PPAR? signaling pathways in the regulation of blood pressure and hypertensive vascular remodeling. The successful implementation of these goals should lead to a better understanding of endogenous signaling actions of the model nitroalkene, OA-NO2, in the vasculature and will set strong basis for new perspectives on rational drug design and development of nitroalkene derivatives with antihypertensive and antidiabetic properties. NARRATIVE It has been well documented that cardiovascular complications of diabetes account for 75% of all deaths in patients with type 2 diabetes. Hypertension occurs approximately twice as frequently in patients with diabetes compared with non-diabetic individuals. Although it is clear that the state of diabetes confers an increased risk of cardiovascular events, the mechanism by which metabolic perturbations influence vascular function and structure remain to be further defined. The successful implementation of this proposal should lead to a better understanding of endogenous signaling actions of nitroalkenes in the vasculature and will set strong basis for new perspectives on rational drug design and development of nitroalkene derivatives with antihypertensive and antidiabetic properties.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL089544-05
Application #
8240386
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
Mcdonald, Cheryl
Project Start
2008-04-01
Project End
2013-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
5
Fiscal Year
2012
Total Cost
$367,360
Indirect Cost
$119,860
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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