Adenosine is an important regulator of myocardial oxygen supply-demand balance through its role in coronary vasodilatation. Adenosine inhibits collagen-induced platelet aggregation and vascular smooth muscles (VSM) cell proliferation, and decrease cholesterol deposition in the arterial wall, effects which have long bee speculated to attenuate progression of atherosclerosis. All these effects depend on the binding of this metabolite to specific receptors, as documented by pharmacological studies. The importance of adenosine and its receptors for vascular function was further established by our recent studies, which have shown that adenosine receptors mediate a significant up-regulation of the matrix proteins elastin and lysyl oxidase in VSM cells. A complete understanding of the control of the biological activities of adenosine in the context of vascular function and progression of atherosclerosis, and the development of novel therapeutic approaches, would require identification and characterization of the genes encoding its receptors. Our analyses indicate that VSM cells express low levels of the brain isoform of the A2a-type adenosine receptor which mediates stimulation of adenylyl cyclase, as revealed by RT-PCR. We find, however, that rat VSM cells express high levels of an A3 adenosine receptor which mediates inhibition of adenylyl cyclase. The level of this receptor mRNA is altered by agents such as nitric oxide and Insulin Growth Factor-I(IGF-I). Our preliminary data also suggest that the level of expression of the A3 adenosine receptor, when modulated by antisense oligonucleotides, has an important role in determining the steady state concentration of cAMP and c-fos in VSM cells. Our overall hypothesis is that the regulation of expression of A3 adenosine receptor gene and the relative levels of expression of the inhibitory and stimulatory adenosine receptors in VSM play a vital role in vascular function.
Four specific aims are proposed to test this hypothesis.
Aim 1. To characterize the pharmacological properties of the A3 adenosine receptor expressed in VSM cells.
Aim 2. To characterize A3 adenosine receptor genome regulatory elements responsible for gene activation in VSM cells and to identify potential cDNAs encoding the murine VSM A2 adenosine receptors.
Aim 3. To determine the mechanism of induction of matrix proteins by the adenosine receptor-mediated increase in cAMP.
Aim 4. To assess the role of the inhibitory and stimulatory adenosine receptors in determining vascular function and matrix gene expression in transgenic and knock out mice. These studies should shed new light on the role of adenosine receptor expression in the pathogenesis of vascular dysfunction.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL013262-27
Application #
6202151
Study Section
Project Start
1999-12-01
Project End
2000-11-30
Budget Start
1998-10-01
Budget End
1999-09-30
Support Year
27
Fiscal Year
2000
Total Cost
$617,188
Indirect Cost
Name
Boston University
Department
Type
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118
Lucero, Héctor A; Mäki, Joni M; Kagan, Herbert M (2011) Activation of cellular chemotactic responses to chemokines coupled with oxidation of plasma membrane proteins by lysyl oxidase. J Neural Transm (Vienna) 118:1091-9
Chen, Hongjie; Koupenova, Milka; Yang, Dan et al. (2011) Regulation of MMP-9 expression by the A2b adenosine receptor and its dependency on TNF-? signaling. Exp Hematol 39:525-30
Yang, D; Chen, H; Koupenova, M et al. (2010) A new role for the A2b adenosine receptor in regulating platelet function. J Thromb Haemost 8:817-27
Grimsby, Jessica L; Lucero, Hector A; Trackman, Philip C et al. (2010) Role of lysyl oxidase propeptide in secretion and enzyme activity. J Cell Biochem 111:1231-43
St Hilaire, Cynthia; Carroll, Shannon H; Chen, Hongjie et al. (2009) Mechanisms of induction of adenosine receptor genes and its functional significance. J Cell Physiol 218:35-44
Wu, Xiaoyan; Kong, Xiaocen; Luchsinger, Larry et al. (2009) Regulating the activity of class II transactivator by posttranslational modifications: exploring the possibilities. Mol Cell Biol 29:5639-44
Chen, Hongjie; Yang, Dan; Carroll, Shannon H et al. (2009) Activation of the macrophage A2b adenosine receptor regulates tumor necrosis factor-alpha levels following vascular injury. Exp Hematol 37:533-8
Chandrasekharan, Bindu P; Kolachala, Vasantha L; Dalmasso, Guillaume et al. (2009) Adenosine 2B receptors (A(2B)AR) on enteric neurons regulate murine distal colonic motility. FASEB J 23:2727-34
Kolachala, Vasantha L; Vijay-Kumar, Matam; Dalmasso, Guillaiume et al. (2008) A2B adenosine receptor gene deletion attenuates murine colitis. Gastroenterology 135:861-70
Liu, Libin; Brown, Dennis; McKee, Mary et al. (2008) Deletion of Cavin/PTRF causes global loss of caveolae, dyslipidemia, and glucose intolerance. Cell Metab 8:310-7

Showing the most recent 10 out of 164 publications