Endogenous Adenosine Selectively Modulates Oxidant Stressviathe A₁Receptor in Ischemic Hearts

Abstract

We tested the impact of A 1 adenosine receptor (AR) deletion on injury and oxidant damage in mouse hearts subjected to 25-min ischemia=45-min reperfusion (I=R). Wild-type hearts recovered *50% of contractile function and released 8.2 AE 0.7 IU=g of lactate dehydrogenase (LDH). A 1 AR deletion worsened dysfunction and LDH efflux (15.2 AE 2.6 IU=g). Tissue cholesterol and native cholesteryl esters were unchanged, whereas cholesteryl ester-derived lipid hydroperoxides and hydroxides (CE-O(O)H; a marker of lipid oxidation) increased threefold, and a-tocopherylquinone [a-TQ; oxidation product of a-tocopherol (a-TOH)] increased sixfold. Elevations in a-TQ were augmented by two-to threefold by A 1 AR deletion, whereas CE-O(O)H was unaltered. A 1 AR deletion also decreased glutathione redox status ([GSH]=[GSSG + GSH]) and enhanced expression of the antioxidant response element heme oxygenase-1 (HO-1) during I=R: fourfold elevations in HO-1 mRNA and activity were doubled by A 1 AR deletion. Broad-spectrum AR agonism (10 mM 2-chloroadenosine; 2-CAD) countered effects of A 1 AR deletion on oxidant damage, HO-1, and tissue injury, indicating that additional ARs (A 2A , A 2B , and=or A 3 ) can mediate similar actions. These data reveal that local adenosine engages A 1 ARs during I=R to limit oxidant damage and enhance outcome selectively. Control of a-TOH=a-TQ levels may contribute to A 1 AR-dependent cardioprotection.

Differential Effect of Phosphodiesterase-3 Inhibitors on Sympathetic Hyperinnervation in Healed Rat Infarcts

“…Previous studies have shown that adenosine exerts as an antioxidant through activation of the A1 receptor in ischemic myocardium. 28 Our results were not consistent with the previous findings of Park et al, 29 who showed that the increased cAMP level with cilostazol, but not adenosine, is directly coupled to the reduction in NAD(P)H-dependent superoxide production in human endothelial cells. If cAMP plays a role in attenuating superoxide production, rats treated with milrinone should have had lower levels of superoxide compared with cilostazol-treated rats, which was not the case.…”

Adenosine Kinase: Exploitation for Therapeutic Gain

“…Adenosine exerts a variety of cardioprotective effects, which are largely based on the activation of A 1 Rs (Hedqvist and Fredholm, 1979). Those cardioprotective effects include protection against ischemia/ reperfusion injury (Mubagwa and Flameng, 2001;Peart and Headrick, 2007), reduction of oxidative stress (Narayan et al, 2001;Reichelt et al, 2009), and attenuation of hypertrophy and heart failure (Liao et al, 2003;Lu et al, 2008;Xu et al, 2008). Since the antihypertrophic effects of adenosine cannot completely be abrogated by genetic deletion or pharmacological blockade of the adenosine receptors Fassett et al, 2011), the intracellular metabolism of adenosine in cardiomycytes might play a critical role.…”

Extracellular Adenosine: A Safety Signal That Dampens Hypoxia-Induced Inflammation During Ischemia

“…At present, four different ARs have been described that represent G-protein coupled membrane-spanning receptors. Signaling events through these receptors have been associated with a wide range of biological functions, such as the regulation of the heart-rate (64,76,92,120), vascular tone (6), the sensation of pain, and the regulation of immune functions of the innate or adaptive immune system (28,85,(104)(105)(106)(107). For example, the signaling effects of extracellular adenosine signaling are utilized in a clinical setting when treating patients with supraventricular tachycardia.…”

“…Several very elegant studies from the laboratory of John Headrick in collaboration with Michael Blackburn demonstrate a functional role of the A1AR in cardio-protection from ischemia. While mice with overexpression of the A1AR are protected from ischemia, A1AR knockout mice have attenuated ischemia tolerance (76,92,93). Functional studies indicate that intrinsically activated A1ARs appear to enhance postischemic contractility and limit cardiac cell death (93).…”