Evidence of tanscriptional and tanslational components in anti‐ischemic effects of adenosine

Abstract

Adenosine protects against myocardial ischemic injury via poorly defined mechanisms. We examined effects of inhibition of gene transcription, mRNA translation, and mitochondrial K ATP channels on cardioprotective effects of adenosine in mouse hearts subjected to 20-min ischemia. Adenosine treatment reduced postischemic lactate dehydrogenase efflux (indicating necrosis) from 2472 to 971 IU/g, and postischemic diastolic contracture from 2172 to 572 mm Hg, and enhanced postischemic ventricular pressure development from 7273 to 13574 mm Hg. The antinecrotic response was reduced E50% by inhibition of protein translation (10 mM cycloheximide, CHX), unaltered by inhibition of transcription (20 mM actinomycin D, Act-D), and abrogated by mitochondrial K ATP channel inhibition (100 mM 5-hydroxydecanoate, 5-HD). In contrast, protection against contractile dysfunction was reduced but not eliminated by CHX, Act-D, and 5-HD, and inhibitory effects CHX and Act-D were not additive with those of 5-HD, supporting a common mechanistic path. Inhibitory effects of Act-D were mimicked by 1.5 mM a-amanitin. These data provide evidence that adenosine limits necrosis in a mito K ATP channel-dependent manner involving protein translation. The translational component is not dependent upon mRNA transcription. Adenosine also substantially reduces contractile dysfunction via a pathway involving mitochondrial K ATP channel activation, protein translation, and mRNA transcription. Protection independent of this path was also evident. Thus, distinct signaling pathways appear to be involved in adenosine-mediated protection against postischemic necrosis and contractile dysfunction. Drug Dev. Res. 58:454-460, 2003.

Acute adenosinergic cardioprotection in ischemic-reperfused hearts

“…Although not entirely surprising, many of these changes are consistent with the observed ischemia-tolerant phenotype (e.g., modulation of pro-and antiapoptotic genes and genes for structural and contractile proteins). In more direct analysis, putative inhibitors of transcription and translation can modify acute cardioprotective actions of adenosine (118). Collectively, these studies support a role for gene transcription and/or protein synthesis in the acute effects of adenosine receptor activation.…”

“…Inhibitory effects of 5-HD may reflect antagonism of these actions and/or activation to 5-HD-CoA with modulation of fatty acid oxidation and mitochondrial metabolism (97). Given the common effects of adenosine and diazoxide (77,207,210,228) and inhibition of adenosinergic protection by 5-HD (113,118,207,210,228), it is possible acute adenosinergic protection involves the above-mentioned inhibitory actions on ROS generation, mitochondrial metabolism, and nucleotide-dependent enzymatic activity as opposed to mitoK ATP activation. In this respect, a number of investigations verify that adenosine receptor activation modifies mitochondrial energy metabolism (2, 43, 79, 112) and inhibits ROS generation (210) in ischemic-reperfused myocardium.…”

“…Curiously, the more recent of these studies employed high levels of an A 1 -selective agonist to examine the putative A 2 AR-mediated response. Because cardioprotective NHE inhibition is mediated by mitoK ATP channels (206), because adenosine receptors also protect via mitoK ATP channel-dependent (or diazoxide/5-HD-dependent) processes (113,118,207,210,228,282), and because adenosine receptor signaling is coupled to NHE modulation in cardiac and noncardiac tissues (11, 59, 60), it seems probable that NHE modulation may be involved in adenosinergic protection. This possibility deserves more direct attention.…”