The broad long-term objective of this proposal is to establish heme oxygenase-1 (HO-1)-derived carbon monoxide (CO) as a biologically important gas that promotes homeostasis following arterial injury. We have recently demonstrated that gene transfer of HO-1 or the exogenous administration of CO blocks neointima formation following arterial injury, and that this is associated with a marked decrease in vascular smooth muscle cell growth and collagen deposition. We now propose to extend these studies and establish the significance and mechanism by which CO regulates endothelial cell (EC) function following arterial injury and in vascular disease. The central hypothesis of this proposal is that CO plays a critical role in promoting EC growth following arterial injury and that CO reverses endothelial dysfunction in hyperhomocysteinemia and diabetes. We further propose that CO mediates these effects via the activation of eNOS.
In aim 1, we will examine the effect of endogenously derived or exogenously administered CO in regulating EC function and regrowth following arterial injury. These studies will investigate the effect of CO on EC proliferation, migration, apoptosis, and senescence, and determine whether the eNOS-mediated release of NO contributes to the biological actions of CO. We will also examine the mechanism by which CO regulates eNOS activity exploring possible transcriptional, postranscriptional, and posttranslational modes of regulation. In addition, we will investigate the effect of HO-1 gene transfer, HO-1 gene deletion, or CO administration on endothelial function and regrowth following carotid artery injury in rodents.
In aim 2, we will determine whether the induction of HO-1 and CO synthesis in hyperhomocysteinemia functions in an adaptive manner to preserve endothelial function and blood pressure.
In aim 3, we will investigate whether the dysregulation of CO synthesis in diabetes contributes to the development of endothelial dysfunction. In addition, we will examine whether restoration of endogenous CO synthesis or exogenous delivery of CO corrects endothelial function and regrowth following arterial injury. It is anticipated that these studies will establish the HO-1/CO system as a critical regulator of EC function, and will identify CO as a novel therapeutic modality in preventing endothelial dysfunction and vascular disease.

Public Health Relevance

Cardiovascular disease and stroke claims more lives and costs more money than any other disease in the United States of America. Studies in our laboratory have identified the gas carbon monoxide as a critical regulator of blood flow and blood pressure. This project will explore the possible therapeutic application of low doses of carbon monoxide in preventing the blockage of arteries and in treating high blood pressure.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL059976-13
Application #
8399024
Study Section
Cardiovascular Differentiation and Development Study Section (CDD)
Program Officer
Charette, Marc F
Project Start
1998-12-01
Project End
2014-12-31
Budget Start
2013-01-01
Budget End
2014-12-31
Support Year
13
Fiscal Year
2013
Total Cost
$315,060
Indirect Cost
$103,002
Name
University of Missouri-Columbia
Department
Pharmacology
Type
Schools of Medicine
DUNS #
153890272
City
Columbia
State
MO
Country
United States
Zip Code
65211
Peyton, Kelly J; Liu, Xiao-ming; Durante, William (2016) Prolonged cyclic strain inhibits human endothelial cell growth. Front Biosci (Elite Ed) 8:205-12
Liu, Xiao-Ming; Durante, Zane E; Peyton, Kelly J et al. (2016) Heme oxygenase-1-derived bilirubin counteracts HIV protease inhibitor-mediated endothelial cell dysfunction. Free Radic Biol Med 94:218-29
Higashi, Yusuke; Sukhanov, Sergiy; Shai, Shaw-Yung et al. (2016) Insulin-Like Growth Factor-1 Receptor Deficiency in Macrophages Accelerates Atherosclerosis and Induces an Unstable Plaque Phenotype in Apolipoprotein E-Deficient Mice. Circulation 133:2263-78
Johnson, Fruzsina K; Peyton, Kelly J; Liu, Xiao-Ming et al. (2015) Arginase promotes endothelial dysfunction and hypertension in obese rats. Obesity (Silver Spring) 23:383-90
Durante, William (2015) Bilirubin: striking gold in diabetic vasculopathy? Diabetes 64:1506-8
Chang, Chao-Fu; Liu, Xiao-Ming; Peyton, Kelly J et al. (2014) Heme oxygenase-1 counteracts contrast media-induced endothelial cell dysfunction. Biochem Pharmacol 87:303-11
Wang, Walter Z; Jones, Allan W; Wang, Meifang et al. (2013) Preconditioning with soluble guanylate cyclase activation prevents postischemic inflammation and reduces nitrate tolerance in heme oxygenase-1 knockout mice. Am J Physiol Heart Circ Physiol 305:H521-32
Liu, Xiao-ming; Peyton, Kelly J; Durante, William (2013) Physiological cyclic strain promotes endothelial cell survival via the induction of heme oxygenase-1. Am J Physiol Heart Circ Physiol 304:H1634-43
Peyton, Kelly J; Liu, Xiao-ming; Yu, Yajie et al. (2012) Activation of AMP-activated protein kinase inhibits the proliferation of human endothelial cells. J Pharmacol Exp Ther 342:827-34
Liu, Xiao-ming; Peyton, Kelly J; Wang, Xinhui et al. (2012) Sildenafil stimulates the expression of gaseous monoxide-generating enzymes in vascular smooth muscle cells via distinct signaling pathways. Biochem Pharmacol 84:1045-54

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