Endothelium-dependent vasodilation plays an important role in the control of coronary vascular tone. An endothelium-derived hyperpolarization factor, epoxyeicosanoids (EETs) and an endothelium- derived relaxation factor, nitric oxide (NO) have been reported to activate K+ channel in vascular smooth muscle and dilate coronary vessels. However, the mechanism by which EETs and NO activate K+ channels remains unknown. Recently, several important observations suggest that intracellular ADP-riboses may serve as a new second messenger to regulate cell functions in non-vascular tissues. Our preliminary findings also indicate that cyclic ADP-ribose and ADP- ribose may participate in the gating of K+ channel in coronary vascular smooth muscle and EETs alter the metabolism of these signaling nucleotides. The purpose of the proposed studies is to determine the role of cyclic ADP-ribose and ADP-ribose in the gating of potassium (K+) channels in vascular smooth muscle cells isolated from small coronary arteries and the contribution of these nucleotides to the effect of endogenous vasodilators such as EETs and NO, on K+ channel activity and vascular tone. We will first characterize the enzymatic pathways of cADP-R and ADP-R metabolism in coronary vascular smooth muscle and define the kinetic properties and regulatory mechanism of the key enzymes in these pathways. These novel nucleotides will be measured using ion-pair reverse phase HPLC technique and their structure will be identified using mass spectrometry. A lymphocyte differentiate antigen, CD38 which has multiple activities including the production and hydrolysis of cyclic ADP-ribose will be detected in vascular smooth muscle of coronary arteries. We will determine the role of cyclic ADP-ribose and ADP-ribose in the gating of K+ channels and define the type of K+ channels that is gated by cyclic ADP-ribose and ADP-ribose using patch clamp technique. We will also explore the molecular mechanism by which cyclic ADP-ribose and ADP-ribose gate K+ channels. Finally we will determine whether cyclic ADP-ribose or ADP- ribose contributes to the effect of endothelium-derived vasodilators. The role of cyclic ADP-ribose and ADP-ribose in K+ channel activation induced by EETs and NO will be examined. These studies will demonstrate a new signaling pathway for the action of endothelium-derived vasodilators and contribute to our understanding of cellular and molecular mechanism gating K+ channels and regulating coronary vascular tone.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29HL057244-02
Application #
2609383
Study Section
Experimental Cardiovascular Sciences Study Section (ECS)
Project Start
1997-01-01
Project End
2000-11-30
Budget Start
1997-12-01
Budget End
1998-11-30
Support Year
2
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Medical College of Wisconsin
Department
Pharmacology
Type
Schools of Medicine
DUNS #
073134603
City
Milwaukee
State
WI
Country
United States
Zip Code
53226
Chen, Yu; He, Xingxiang; Yuan, Xinxu et al. (2018) NLRP3 Inflammasome Formation and Activation in Nonalcoholic Steatohepatitis: Therapeutic Target for Antimetabolic Syndrome Remedy FTZ. Oxid Med Cell Longev 2018:2901871
Yuan, Xinxu; Wang, Lei; Bhat, Owais M et al. (2018) Differential effects of short chain fatty acids on endothelial Nlrp3 inflammasome activation and neointima formation: Antioxidant action of butyrate. Redox Biol 16:21-31
Bao, Jun-Xiang; Zhang, Qin-Fang; Wang, Mi et al. (2017) Implication of CD38 gene in autophagic degradation of collagen I in mouse coronary arterial myocytes. Front Biosci (Landmark Ed) 22:558-569
Li, Guangbi; Chen, Zhida; Bhat, Owais M et al. (2017) NLRP3 inflammasome as a novel target for docosahexaenoic acid metabolites to abrogate glomerular injury. J Lipid Res 58:1080-1090
Koka, Saisudha; Xia, Min; Chen, Yang et al. (2017) Endothelial NLRP3 inflammasome activation and arterial neointima formation associated with acid sphingomyelinase during hypercholesterolemia. Redox Biol 13:336-344
Conley, Sabena M; Abais, Justine M; Boini, Krishna M et al. (2017) Inflammasome Activation in Chronic Glomerular Diseases. Curr Drug Targets 18:1019-1029
Boini, Krishna M; Xia, Min; Koka, Saisudha et al. (2017) Sphingolipids in obesity and related complications. Front Biosci (Landmark Ed) 22:96-116
Chen, Yang; Yuan, Ming; Xia, Min et al. (2016) Instant membrane resealing in nlrp3 inflammmasome activation of endothelial cells. Front Biosci (Landmark Ed) 21:635-50
Xu, Ming; Zhang, Qiufang; Li, Pin-Lan et al. (2016) Regulation of dynein-mediated autophagosomes trafficking by ASM in CASMCs. Front Biosci (Landmark Ed) 21:696-706
Xia, Min; Abais, Justine M; Koka, Saisudha et al. (2016) Characterization and Activation of NLRP3 Inflammasomes in the Renal Medulla in Mice. Kidney Blood Press Res 41:208-21

Showing the most recent 10 out of 69 publications