An adenosinergic positive feedback loop extends pharmacological cardioprotection duration.

Background And Purpose: Adenosine receptor activation induces delayed, sustained cardioprotection against ischaemia-reperfusion (IR) injury (24-72 h), but the mechanisms underlying extended cardioprotection duration remain unresolved. We hypothesized that a positive feedback loop involving adenosine receptor-induced proteasomal degradation of adenosine kinase (ADK) and decreased myocardial adenosine metabolism extends the duration of cardioprotection.

Experimental Approach: Mice were administered an ADK inhibitor, ABT-702, to induce endogenous adenosine signalling.

Adenosine kinase (ADK) inhibition with ABT-702 induces ADK protein degradation and a distinct form of sustained cardioprotection.

Pharmacological inhibition of adenosine kinase (ADK), the major route of myocardial adenosine metabolism, can elicit acute cardioprotection against ischemia-reperfusion (IR) by increasing adenosine signaling. Here, we identified a novel, extended effect of the ADK inhibitor, ABT-702, on cardiac ADK protein longevity and investigated its impact on sustained adenosinergic cardioprotection. We found that ABT-702 treatment significantly reduced cardiac ADK protein content in mice 24-72 h after administration (IP or oral).

Adenosine kinase attenuates cardiomyocyte microtubule stabilization and protects against pressure overload-induced hypertrophy and LV dysfunction.

Adenosine exerts numerous protective actions in the heart, including attenuation of cardiac hypertrophy. Adenosine kinase (ADK) converts adenosine to adenosine monophosphate (AMP) and is the major route of myocardial adenosine metabolism, however, the impact of ADK activity on cardiac structure and function is unknown. To examine the role of ADK in cardiac homeostasis and adaptation to stress, conditional cardiomyocyte specific ADK knockout mice (cADK) were produced using the MerCreMer-lox-P system.