Mechanisms of cardiac protection with Overexpression of A₁ adenosine receptors

Abstract

Myocardial damage from ischemia/reperfusion injury can be minimized through endogenous protective mechanisms, including activation of A 1 adenosine receptors. Transgenic mice with cardiac-specific A 1 adenosine receptor overexpression (A 1 AR Trans) have demonstrated functional and metabolic tolerance to in vitro and in vivo myocardial ischemia/reperfusion injury. The purpose of this investigation is to examine the role of p38 MAP kinase in A 1 receptor-mediated cardioprotection. Activation of p38 MAPK by A 1 adenosine receptor stimulation was evaluated in neonatal rat cardiomyocytes subjected to simulated ischemia. A 1 activation by cyclopentyladenosine decreased cell death and simultaneously enhanced p38 phosphorylation by simulated ischemia. The role of p38 MAP kinase activation in cardioprotection with A 1 adenosine receptor overexpression was evaluated in isolated perfused hearts from A 1 AR Trans mice subjected to 20 min ischemia and 30 min reperfusion. Inhibition of p38 MAPK activity with 10 mM SB-203580 prior to ischemia and during reperfusion decreased postischemic total functional recovery in A 1 AR Trans hearts from 54 7 1 to 2777% of maximal and increased final EDP from 1073 mmHg to 3478 mmHg. A 1 adenosine receptor-mediated activation of p38 MAP kinase in cardiomyocytes is involved in the protection of cells from ischemic death. Tolerance to ischemic injury by A 1 receptor overexpression is dependent upon activation of p38 MAPK. These findings suggest that adenosine A 1 mediated cardioprotection in transgenic mice involves activation of the p38 MAP kinase cascade. Drug Dev.

Effects of targeted deletion of A1 adenosine receptors on postischemic cardiac function and expression of adenosine receptor subtypes

“…These findings support the established cardioprotective role of A 1 ARs in ischemia-reperfusion (7,17,33), whether it occurs by endogenous activation (35,48) or exogenously through acute application of high-dose adenosine agonists (7,24,33). The decreased tolerance to ischemia-reperfusion in A 1 KO hearts contrasts with enhanced ischemic tolerance in hearts overexpressing A 1 ARs (11,22,29,30,36). In line with recent data (23,38), the nature of impaired postischemic function in A 1 KO hearts was multifaceted with lower initial and sustained developed pressure, lower initial and sustained coronary flow, and worsened diastolic dysfunction through all but the initial phase of reperfusion.…”

“…Indeed, with the use of this combined approach, data from the A 1 knockout (A 1 KO) model recently developed by Sun et al (42) affirm a protective role of A 1 AR activation in renal ischemia-reperfusion (27), but the effects of A 1 deletion on the heart and vasculature are only beginning to be characterized (23,38,45,46). Moreover, the appropriate interpretation of data from studies using these models requires a determined effort to evaluate in parallel the phenotypic, and potentially unanticipated genotypic, alterations that may occur as a consequence of targeted genetic manipulation (1,11,22); that is, the functional genomics of gene-modified models must be assessed, preferably within the context of conditional settings of interest, e.g., ischemia-reperfusion, to optimize the insight gained by using them.…”

Microelectrode Sensing of Adenosine/Adenosine‐5′‐triphosphate with Fast‐Scan Cyclic Voltammetry

“…For example, ATP is located in platelets as well as neurons, where it can be released in an activity dependent manner [3]. Adenosine is thought to be protective, particularly to cardiac cells [4] and neurons [2] after ischemic events. The major breakdown of adenosine is by adenosine deaminase to form inosine.…”