Abstract
Introduction: Membrane-released arachidonic acid (AA) is metabolized via cyclooxygenase pathway to form prostanoids, including thromboxane, prostacyclin and prostaglandin E2. Aspirin suppresses platelet synthesis of thromboxane, rendering its first-line use for anti-thrombosis in patients with acute myocardial ischemia. We report that endogenous PGE2 protects against myocardial ischemia-reperfusion (MI/R) injury (Nat Commun. 2019;10(1):1888). The impact of AA administration while suppressing thromboxane on MI/R injury is unknown. Methods and Results: C57BL/6J mice were treated intravenously with vehicle, AA, aspirin, or their combination and then subjected to 30min coronary artery ligation and 24hr reperfusion. Cardiac function was assessed by ultrasonography and infraction size quantified by TTC staining. Cardiac microcirculation was assessed by laser doppler flow and vasomotor reactivity determined with isolated coronary arteries. Single treatment with AA at an optimized dose of 0.1mg/Kg, or combined with aspirin at a dose of 10mg/Kg that allowed sufficient suppressing of platelet activation over 24hr, decreased infarct size and improved heart function. Impressively, combination of AA with aspirin provided additional cardioprotection compared with either single treatment. While aspirin, not AA, ameliorated microvascular obstruction following MI/R injury, co-administration of AA and aspirin further increased coronary microcirculatory blood perfusion with improved vascular permeability compared with aspirin alone. MI/R impaired endothelium-dependent dilatation of coronary arteries, and the dual treatment, not AA or ASA alone, increased coronary artery relaxation. Cardiac infiltrated neutrophils and platelet-neutrophil aggregates were also reduced by the combination treatment, consistent with a suppressed leukocyte-ECs adhesion as assessed in vitro. Conclusions: AA and aspirin synergistically protect against MI/R injury and this is attributable to suppressed neutrophil inflammation and improved microvascular obstruction. AA might be used as an adjunct therapy to aspirin in patients with acute myocardial infarction.
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