Atherogenesis is a complex process that appears to be initiated by alterations of endothelium. An elevated level of plasma low-density lipoproteins (LDL) is thought to be responsible for the development of atherosclerosis because the characteristics of LDL-induced endothelium dysfunction are very similar to those observed in hypercholesterolemic and atherosclerotic subjects. Indeed, exposure of normal large coronary arteries to pathological concentrations of LDL inhibits endothelium- dependent vasorelaxation within minutes. However, it is unclear whether coronary microvessels (<150 MU m) are also susceptible to LDL. This issue is important because these microvessels not only contribute over 70% of coronary resistance but also play a major role in the regulation of coronary blood flow. Interestingly, many studies have shown that administration of a high dose of L-arginine normalizes atherosclerosis- and LDL-induced vascular dysfunction. Since L-arginine is a biological precursor for nitric oxide (NO) synthesis, these results may suggest that the observed vascular dysfunction is due to the impairment of NO synthesis and/or release during LDL exposure. However, the underlying mechanism responsible for this impairment has not been identified, especially at the microcirculatory level. In addition, the mechanism of restoring vascular function by L-arginine is also unclear. Therefore, it is hypothesized in this proposal that the elevated LDL, especially oxidized LDL, alters L- arginine transport and/or L-arginine/NO metabolism in the endothelium and thus leads to vascular dysfunction due to the impairment of NO synthesis and/or release. To test this hypothesis, the experiments are designed: I) to demonstrate conclusively that the deficiency in endothelial release of NO during LDL exposure is responsible for the vascular dysfunction, 2) to determine the alterations of L-arginine transport and metabolism toward the synthesis of NO during LDL exposure, and 3) to delineate the mechanism(s) of restoring vascular function by the administration of L-arginine. To achieve these goals, we will use both isolated arterioles (<150 MU m) and cultured endothelial cells from the porcine coronary microcirculation as experimental models. The isolated arterioles will be cannulated and pressurized for functional study. The cultured cells will be used to probe the mechanism of alteration of L-arginine/NO metabolism. The intact vessel and cultured cell studies will complement each other to address the relationship between vascular function and endothelial L-arginine/NO metabolism during exposure to atherogenic agents. Results from these studies will provide valuable information toward our understanding of the mechanism of vascular dysfunction during the development of atherosclerosis. In addition, elucidation of anti-atherogenic effect of L- arginine may provide a foundation for future therapeutic manipulation of vascular function during hypercholesterolemia and/or atherosclerosis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL055524-05
Application #
6389535
Study Section
Special Emphasis Panel (ZRG4-CVB (03))
Program Officer
Goldman, Stephen
Project Start
1997-04-01
Project End
2003-03-31
Budget Start
2001-04-01
Budget End
2003-03-31
Support Year
5
Fiscal Year
2001
Total Cost
$208,655
Indirect Cost
Name
Texas A&M University
Department
Physiology
Type
Schools of Medicine
DUNS #
City
College Station
State
TX
Country
United States
Zip Code
77845
Zhang, Cuihua; Hein, Travis W; Wang, Wei et al. (2006) Activation of JNK and xanthine oxidase by TNF-alpha impairs nitric oxide-mediated dilation of coronary arterioles. J Mol Cell Cardiol 40:247-57
Zhang, Cuihua; Hein, Travis W; Wang, Wei et al. (2003) Divergent roles of angiotensin II AT1 and AT2 receptors in modulating coronary microvascular function. Circ Res 92:322-9
Thengchaisri, Naris; Kuo, Lih (2003) Hydrogen peroxide induces endothelium-dependent and -independent coronary arteriolar dilation: role of cyclooxygenase and potassium channels. Am J Physiol Heart Circ Physiol 285:H2255-63
Rivers, R J; Hein, T W; Zhang, C et al. (2001) Activation of barium-sensitive inward rectifier potassium channels mediates remote dilation of coronary arterioles. Circulation 104:1749-53
Hein, T W; Platts, S H; Waitkus-Edwards, K R et al. (2001) Integrin-binding peptides containing RGD produce coronary arteriolar dilation via cyclooxygenase activation. Am J Physiol Heart Circ Physiol 281:H2378-84
Chang, C I; Liao, J C; Kuo, L (2001) Macrophage arginase promotes tumor cell growth and suppresses nitric oxide-mediated tumor cytotoxicity. Cancer Res 61:1100-6
Hein, T W; Liao, J C; Kuo, L (2000) oxLDL specifically impairs endothelium-dependent, NO-mediated dilation of coronary arterioles. Am J Physiol Heart Circ Physiol 278:H175-83
Chang, C I; Zoghi, B; Liao, J C et al. (2000) The involvement of tyrosine kinases, cyclic AMP/protein kinase A, and p38 mitogen-activated protein kinase in IL-13-mediated arginase I induction in macrophages: its implications in IL-13-inhibited nitric oxide production. J Immunol 165:2134-41
Hein, T W; Kuo, L (1998) LDLs impair vasomotor function of the coronary microcirculation: role of superoxide anions. Circ Res 83:404-14
Chang, C I; Liao, J C; Kuo, L (1998) Arginase modulates nitric oxide production in activated macrophages. Am J Physiol 274:H342-8

Showing the most recent 10 out of 11 publications