Adenosine-mediated cardioprotection in the aging myocardium

Abstract

With aging, it appears the heart's ability to withstand injury declines markedly. Unfortunately, the incidence of ischemic disorders increases dramatically with age. Though the genesis of the ischemia-intolerant phenotype is incompletely understood (and likely multi-factorial), it may involve changes in intrinsic cardioprotective responses. In this respect we and others have interrogated the role of the adenosine receptor (AR) system in dictating ischemic tolerance and the impact of age on AR-mediated cardioprotection. It is intriguing to note ARs impact on many processes implicated in myocardial 'aging': adenosine counters Ca2+ influx and oxidant injury, modifies substrate metabolism to improve tolerance, is pro-angiogenic, inhibits myocardial fibrosis, and can limit apoptosis. Thus, dysregulation of the AR system could contribute to many features of aged hearts (including ischemic intolerance). The latter is borne out by observations that AR-mediated protective responses decline with intrinsic tolerance and that transgenic manipulation of the AR system restores intrinsic tolerance and protective responses in aged hearts. Mechanisms underlying failure in adenosinergic protection remain undefined. Here we review data on the effects of aging on cardiovascular AR transcription and expression, generation of signal (adenosine formation), and protective signaling coupled to ARs.

ADA*2 Allele of the Adenosine Deaminase Gene May Protect against Coronary Artery Disease

“…It is plausible that *2 allele, encoding for less active enzyme deaminating adenosine, is responsible for increased myocardial adenosine concentrations which exert cardioprotective effects [17,18,19]. However, no evidence of elevated adenosine levels in tissues of ADA*2 carriers is currently available.…”

Clinical cardioprotection and the value of conditioning responses

“…While Teoh et al (214) acquired evidence of a superior effect of ischemic vs. pharmacological Precon, other support for benefit via conditioning pharmacomimetics has been acquired. Adenosine may play a key role in triggering cardioprotection with Precon and Postcon (77,231), although it provides other beneficial effects that may be independent of these responses (166). Trials of adenosine as an adjunctive protective therapy have been successful in limiting postinfarct mortality (116), together with up to a 60% reduction in infarct vs. no treatment (182).…”

“…Although this remains somewhat contentious, as some investigators do report preservation of Precon or related protection in aged hearts (23,123,138), the weight of evidence indicates that age reduces or abrogates Precon responses in humans (2,12,128,136,151,159) and in animal models (1,16,50,56,85,140,186,210,211). Aging also inhibits protection via remote Precon (89), anesthetic Precon (197), in response to GPCR agonists such as adenosine (81,173,186,231) or opioids (164,165), and novel forms of Precon (82). Two recent studies (15, 174) also report that aging abrogates protection with Postcon.…”

Dipyridamole in heart failure due to dilated cardiomyopathy: A pilot study

“…[12] The explanation of all these findings remains unsettled, but it may relate to the long-term positive effects of endogenous adenosine accumulation, possibly extended through an angiogenic, anti-inflammatory, anti-fibrotic, and anti-apoptotic effect. [28,29] Comparison with previous studies…”