Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Teschl, E.
PHARMACOLOGICAL TARGETING OF ADENOSINE KINASE FOR SUSTAINED CARDIOPROTECTION
Humanmedizin; [ Diplomarbeit ] Medizinische Universität Graz; 2023. pp. 51
[OPEN ACCESS]
FullText
- Autor*innen der Med Uni Graz:
- Betreuer*innen:
- Kolesnik Ewald
- Altmetrics:
- Abstract:
- Cardiovascular diseases have a significant global impact on society and healthcare systems and accounted for the majority of Austrian deaths in recent years. Coronary artery disease (CAD) is one of the most prevalent forms of cardiovascular diseases and significantly raises the risk of acute myocardial infarction (AMI). Increasing myocardial adenosine receptor signaling prior to AMI or at reperfusion can diminish myocardial injury. However, the therapeutic utility of adenosine receptor agonists for this issue is limited by the wide tissue distribution of adenosine receptors, strong physiological effects of adenosine signalling in non-target tissues and, above all, the fact that acute AMI are unfortunately unpredictable. The pharmacological inhibition of the major enzyme responsible for myocardial adenosine metabolism, adenosine kinase (ADK), increases cardiomyocyte adenosine release and can thus provide acute cardioprotection against ischaemia-reperfusion injury. Whether these abilities are also applicable for sustained cardioprotection is not known. A novel mechanism of sustained cardioprotection may be induced by adenosine kinase inhibition, which may lead to novel approaches for eliciting the cardioprotective properties of adenosine in the heart. ABT-702 administration increases adenosine receptor-mediated physiological effects and cardioprotection 24 hours after administration, even though the drug had been eliminated by that time. ABT-702 treatment does not alter expression of cardiac adenosine receptors, but unexpectedly, causes a reduction in ADK protein expression that results in sustained cardiomyocyte adenosine release. Dose response studies demonstrated that oral administration of ABT-702 (3mg/kg) also caused ADK degradation that was protective against ischemia-reperfusion injury. Importantly, sustained cardioprotection by ABT-702 was dependent upon increased adenosine receptor signaling just prior to IR, suggesting a novel mechanism of delayed preconditioning. Understanding the mechanism(s) by which ABT-702 decreases cardiac ADK expression could lead to new therapies that provide sustained cardioprotection.