A₁ adenosine receptor overexpression attenuates ischemia-reperfusion-induced apoptosis and caspase 3 activity

Abstract

We tested the hypothesis that myocardial ischemia-reperfusion (I/R)-induced apoptosis is attenuated in transgenic mice overexpressing cardiac A(1) adenosine receptors. Isolated hearts from transgenic (TG, n = 19) and wild-type (WT, n = 22) mice underwent 30 min of ischemia and 2 h of reperfusion, with evaluation of apoptosis, caspase 3 activity, function, and necrosis. I/R-induced apoptosis was attenuated in TG hearts. TG hearts had less I/R-induced apoptotic nuclei (0.88 +/- 0.10% vs. 4.22 +/- 0.24% terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive cells in WT, P< 0.05), less DNA fragmentation (3.30 +/- 0.38-fold vs. 4.90 +/- 0.39-fold over control in WT, P < 0.05), and less I/R-induced caspase 3 activity (145 +/- 25% over nonischemic control vs. 234 +/- 31% in WT, P < 0.05). TG hearts also had improved recovery of function and less necrosis than WT hearts. In TG hearts pretreated with LY-294002 (3 microM) to evaluate the role of phosphosinositol-3-kinase in acute signaling, there was no change in the functional protection or apoptotic response to I/R. These data suggest that cardioprotection with transgenic overexpression of A(1) adenosine receptors involves attenuation of I/R-induced apoptosis that does not involve acute signaling through phosphoinositol-3-kinase.

Acute adenosinergic cardioprotection in ischemic-reperfused hearts

“…Collectively, these studies support a role for gene transcription and/or protein synthesis in the acute effects of adenosine receptor activation. This form of control agrees with adenosine-mediated inhibition of transcriptionally regulated apoptosis postischemia (237,310), possibly via modulating transcription and expression of Bcl-2 and Bax (310).…”

“…Adenosinergic protection has been clearly established as a mechanism for reducing both oncosis (9, 207, 224, 228, 277, 314) and apoptosis (237,310), leading to substantial reductions in infarct size and injury. Whether adenosinergic responses protect against reversible injury is more difficult to ascertain because both forms of injury often coexist in the same model.…”

Pathophysiology of myocardial reperfusion injury: preconditioning, postconditioning, and translational aspects of protective measures

“…This has been supported by reports from other groups (95,196). Recent reports also revealed that adenosine is an endogenous bioactive substance with multiple cardiovascular effects, including a negative inotropic effect, a negative contractile effect, and promotion of coronary blood flow and anti-platelet activity (90), as well as inhibition of apoptosis (158) and enhancement of autophagy (233). However, the role of elevated intramyocardial cAMP levels and PKA activation in cardioprotection of ischemic preconditioning has been reported (110), but they were both shown to be independent of PKC (117,170,176).…”

Adenosine A1 receptor modifies P53 expression and apoptosis in breast cancer cell line Mcf-7

“…This role is mediated by microglia cells (22). But so far, no evidence has been reported that A1 adenosine receptors induce P53 expression and apoptosis, conversely, it has been shown that these receptors decrease apoptotic cell death in some cells (23,24). Our fi ndings oppose K. Sai et al results from astrosytoma RCR-1 cell line which show that A1 adenosine receptor agonist (CHA) induces apoptosis by activating caspase-9 and the ensuing caspase-3 via being linked to A1 adenosine receptor in RCR-1 cells (25).…”