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.
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