Distinct cardioprotective effects of adenosine mediated by differential coupling of receptor subtypes to phospholipases C and D

Abstract

Adenosine released during cardiac ischemia exerts a marked protective effect in the heart that is mediated by the A 1 and A 3 subtypes of adenosine receptors. The signaling pathways activated by these adenosine receptors have now been characterized in a chick embryo ventricular myocyte culture model of cardioprotection against ischemia. Selective A 1 and A 3 receptor agonists were shown to activate phospholipases C and D, respectively, to achieve their distinct cardioprotective effects. The specificity of the A 3 receptor-phospholipase D interaction was also demonstrated in chick embryo atrial myocytes (which do not express endogenous A 3 receptors) that had been transfected with a vector encoding the human A 3 receptor. Activation of both endogenous A 1 and A 3 receptors in ventricular myocytes resulted in a protective response greater than that induced by stimulation of either receptor alone. Agonists that activate both adenosine A 1 and A 3 receptors may thus prove beneficial for the treatment of myocardial ischemia.-Parsons, M., Young, L., Lee, J. E., Jacobson, K. A., Liang, B. T. Distinct cardioprotective effects of adenosine mediated by differential coupling of receptor subtypes to phospholipases C and D. Keywords ischemia; ventricular myocyte; PKC activity; cardioprotectionAdenosine is released in substantial amounts during myocardial ischemia and exerts a marked protective effect in the heart (1). Furthermore, adenosine released during a brief ischemic episode is able to protect the heart against injury during a subsequent period of prolonged ischemia, resulting in a reduction in infarct size (2)(3)(4)(5)(6)(7)(8). Brief exposure of the heart to adenosine, instead of to ischemia, induces a similar protective effect against subsequent ischemia-induced damage. Although both A 1 and A 3 subtypes of adenosine receptors HHS Public AccessAuthor manuscript FASEB J. Author manuscript; available in PMC 2017 August 23. Author Manuscript Author ManuscriptAuthor Manuscript Author Manuscript mediate cardioprotection, the respective protective effects are distinct (9). The signaling mechanisms that underlie these distinct receptor-mediated responses have remained unknown.A culture model for simulating ischemia and cardioprotection has been developed with embryonic chick cardiac ventricular myocytes (5,9,10,11). This model exhibits adenosineinduced protective effects similar to those apparent in the intact heart (4, 6-8, 12, 13). With this cardiac cell model, the objective of the current study was to investigate whether the signaling mechanism underlying the adenosine A 1 receptor-mediated cardioprotective effect differs from that used by the adenosine A 3 receptor. Specifically, the study was aimed at testing the hypothesis that the distinct cardioprotective effects were mediated by differential coupling of adenosine A 1 and A 3 receptors to phospholipase C (PLC) and phospholipase D (PLD), respectively. MATERIALS AND METHODS Preparation of cultured cardiac atrial and ventricular myocytes and simulation of is...

Protective roles of adenosine A1, A2A, and A3receptors in skeletal muscle ischemia and reperfusion injury

“…Although PLC is currently shown to have an important role in mediating the A 3 effect in skeletal muscle, a previous study suggested that PLD, but not PLC, mediated the cardioprotective effect of adenosine A 3 receptors in chick embryo ventricular myocytes (29). The reasons for this apparent difference are not clear; however, several plausible explanations are offered.…”

“…Second, the coupling of adenosine A 3 receptors to PLC vs. PLD may be different in skeletal than in cardiac muscles. Third, our skeletal muscle ischemia-reperfusion injury preparation was an in vivo and intact animal model, whereas the model used by Parsons et al (29) was an isolated cell culture model. The present gene knockout approach rendered all cells completely deficient in PLC-␤2/␤3, including skeletal muscle and circulating immune cells capable of mediating anti-and proinflammatory.…”

The Ral Exchange Factor Rgl2 Promotes Cardiomyocyte Survival and Inhibits Cardiac Fibrosis

“…In different cell systems, RalGDS has been shown to elicit both Ral-dependent and Ral-independent effects [15], [17], [37], [38]. For example, growth factor receptor-induced phospholipase D (PLD) stimulation is mediated by a RalGDS/RalA signaling pathway in HEK293 cells [37], and increasing PLD activation has been shown to enhance PI3K/Akt signaling [39], [40], [41], [42] and mediate cardioprotective effects [43], [44]. Our results demonstrating that Rgl2 enhanced RalA activation support the possibility of a RalA-dependent mechanism for enhancing PI3K/Akt activation in cardiomyocytes.…”

Multivalent dendrimeric and monomeric adenosine agonists attenuate cell death in HL-1 mouse cardiomyocytes expressing the A3 receptor

“…After mouse HL-1 cells were transfected with the hA 3 AR, the receptor protected the cells against H 2 O 2 -induced apoptosis when the protein was activated by 8 . The A 3 AR has significant and unique cardioprotective properties [11,12]. While most previous work used whole animals or cultured cardiomyocytes from various species [11,13], the HL-1 cell line can now be used to study the signaling pathways involved in cardioprotection caused by AR activation.…”

“…Activation of this receptor preconditions cardiomyocytes in culture [11,12], isolated hearts [13], and rabbit hearts in vivo to protect against the damaging effects of ischemia/hypoxia [14]. However, there is still uncertainty over the role of the A 3 AR in cardioprotection.…”