Abstract

This renewal proposal is based on the hypothesis that carbon monoxide, CO, is a previously unrecognized messenger molecule from vascular cells that exerts important autocrine and paracrine actions on vessels and platelets. The objective of the application is to document that CO is a novel, distinctive and biologically active autacoid from smooth muscle and endothelium that arises due to specific humoral and hemodynamic stimuli.
Three aims are: 1. Determine the biological effects of endogenous CO on platelet function and smooth muscle proliferation in vivo and in vitro; 2.Examine the molecular basis of enzyme control between the CO and nitric oxide NO systems, defining the effect of NO on CO production by heme oxygenase and conversely the effect of CO on NO production by NO synthase; and 3. Elucidate the molecular mechanisms of regulation of CO and NO release (from smooth muscle and endothelium) by shear stress and cyclic strain. The goal is to establish CO as an important vascular cell messenger molecule that modulates blood fluidity and may prove to be a target for therapy of vascular disorders.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL036045-15
Application #
6030543
Study Section
Hematology Subcommittee 2 (HEM)
Project Start
1989-09-01
Project End
2002-06-30
Budget Start
1999-07-01
Budget End
2000-06-30
Support Year
15
Fiscal Year
1999
Total Cost
Indirect Cost

  Institution

Name
Baylor College of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
074615394
City
Houston
State
TX
Country
United States
Zip Code
77030

  Publications

Zhang, Daqing; Jiang, Xiaohua; Fang, Pu et al. (2009) Hyperhomocysteinemia promotes inflammatory monocyte generation and accelerates atherosclerosis in transgenic cystathionine beta-synthase-deficient mice. Circulation 120:1893-902
Keswani, Amit N; Peyton, Kelly J; Durante, William et al. (2009) The cyclic GMP modulators YC-1 and zaprinast reduce vessel remodeling through antiproliferative and proapoptotic effects. J Cardiovasc Pharmacol Ther 14:116-24
Tulis, David A (2008) Novel therapies for cyclic GMP control of vascular smooth muscle growth. Am J Ther 15:551-64
Long, Xilin; Schafer, Andrew I (2008) Inhibition of plasminogen activator inhibitor-1 expression in vascular smooth muscle cells by protoporphyrins through a heme oxygenase-independent mechanism. Mol Cell Biochem 312:93-101
Hasan, Rukhsana N; Schafer, Andrew I (2008) Hemin upregulates Egr-1 expression in vascular smooth muscle cells via reactive oxygen species ERK-1/2-Elk-1 and NF-kappaB. Circ Res 102:42-50
Jamaluddin, M D S; Chen, Irene; Yang, Fan et al. (2007) Homocysteine inhibits endothelial cell growth via DNA hypomethylation of the cyclin A gene. Blood 110:3648-55
Jiang, Xiaohua; Yang, Fan; Brailoiu, Eugen et al. (2007) Differential regulation of homocysteine transport in vascular endothelial and smooth muscle cells. Arterioscler Thromb Vasc Biol 27:1976-83
Tan, Hongmei; Jiang, Xiaohua; Yang, Fan et al. (2006) Hyperhomocysteinemia inhibits post-injury reendothelialization in mice. Cardiovasc Res 69:253-62
Liao, Dan; Tan, Hongmei; Hui, Rutai et al. (2006) Hyperhomocysteinemia decreases circulating high-density lipoprotein by inhibiting apolipoprotein A-I Protein synthesis and enhancing HDL cholesterol clearance. Circ Res 99:598-606
Tulis, D A; Keswani, A N; Peyton, K J et al. (2005) Local administration of carbon monoxide inhibits neointima formation in balloon injured rat carotid arteries. Cell Mol Biol (Noisy-le-grand) 51:441-6

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