Functional effects of enhancing or silencing adenosine A_2breceptors in cardiac fibroblasts

Abstract

Cardiac fibroblasts (CF) express adenosine (ADO) receptors, and pharmacological evidence suggests the possible involvement of the A2 (A2a and A2b) receptor (A2aR and A2bR) subtypes in inhibiting cell functions involved in fibrosis. The main objective of this study was to define the contributions of A2a and/or A2b receptors in modulating ADO-induced decreases in CF functions. For this purpose, CF were either treated pharmacologically or had the A2aR or A2bR levels modified through the use of recombinant adenovirus or siRNA. The assessment of mRNA expression in adult rat CF yielded evidence for A1R, A2bR, A2a), and A3R. Endogenously or exogenously enhanced ADO significantly inhibits CF proliferation, collagen, and protein synthesis. A2R and A2aR agonists, although capable of inhibiting CF protein and collagen synthesis, were unable to define the contributions derived from A2aR or A2bR. Overexpression of A2bR in CF yielded significant decreases in basal levels of collagen and protein synthesis and correlated with increases in cAMP levels. However, at higher doses of ADO receptor agonists, significant increases in protein and collagen synthesis were observed. CF with underexpression of A2bR yielded increases in protein and collagen synthesis. In contrast, A2aR underexpression did not modify ADO-induced decreases in CF protein or collagen synthesis. In conclusion, results derived from the molecular manipulation of receptor levels indicate that A2bR are critically involved in ADO-mediated inhibition of CF functions.

Adenosine receptors as therapeutic targets

“…Inhibition of mitosis of rat aortic smooth-muscle cells has been achieved through selective A 2B AR activation 94 . The A 2B ARs are also important for adenosine-mediated inhibition of cardiac fibroblast functions 95 and the stimulation of nitric oxide production during Na + -linked glucose or glutamine absorption 96 . Activation of the A 2B AR promotes angiogenesis by increasing the release of angiogenic factors 2,97 .…”

Signaling pathways involving adenosine A2A and A2B receptors in wound healing and fibrosis

“…Interestingly, this effect is likely mediated by both counteracting the pro-fibrotic role of A 1 and increasing the activation of A 2B receptors, which are anti-inflammatory and have a protective role in cardiac fibrosis via multiple mechanisms. Increased expression of A 2B R leads to a decrease in levels of collagen and protein synthesis, while underexpression of A 2B R yields increased protein and collagen synthesis [45]. In rat cardiac fibroblasts, adenosine activates the A 2B -G s -adenylyl cyclase pathway, and the resultant cAMP reduces collagen synthesis via a PKA-independent, Epacdependent pathway that involves PI3K [46].…”

Ecto-5′-Nucleotidase Deficiency Exacerbates Pressure-Overload–Induced Left Ventricular Hypertrophy and Dysfunction

“…33,34 The role of the A2b receptor is slightly more well defined, as most published data suggest a role in reducing cardiac fibroblast proliferation and collagen synthesis. 8,9 The A2b receptor also plays a role in ameliorating pathological LV tissue remodeling after infarct. 15 Activation of type 2A adenosine receptors, which are highly expressed in the coronary vasculature, can downregulate vascular cell adhesion molecule expression 35 to reduce monocyte adhesion to endothelial cells and vascular inflammation.…”

“…6 Increasing interstitial adenosine levels by blocking adenosine uptake using dipyridamole was also reported to reduce hypertrophy in rats exposed to pressure overload. 7 The antifibrotic effects of adenosine appear to involve activation of A2b receptors, 8,9 whereas a role for cardiac adenosine A1 receptors has been suggested in the adenosine-mediated reduction of cardiomyocyte hypertrophy. 6 Interestingly, endogenous adenosine levels rise during compensatory hypertrophy but are diminished as hearts become decompensated.…”