15-Hydroxyeicosatetraenoic Acid and GPR39 Together Orchestrate Coronary Autoregulation: A Comprehensive Metabolomic Analysis

Abstract Background Coronary autoregulation is the ability of the normal heart to maintain constant coronary blood flow (CBF) over a wide range of coronary driving pressures (CDP). Despite being vital for survival, the mechanism of coronary autoregulation is unknown. We hypothesized that GPR39, present in vascular smooth muscle cells, together with its endogenous agonist 15-hydroxyeicosatetraenoic acid (15-HETE) orchestrate coronary autoregulation. Methods We created coronary stenoses of varying degrees in open-chest, anesthetized dogs where we measured CBF and CDP. In a subset of animals, coronary venous blood was sampled for eicosanoid, adenosine, endothelin-1, polyunsaturated fatty acids, and prostaglandins levels. Stenoses were recreated during intravenous administration of VC108, a specific GPR39 antagonist and systemic, pulmonary, and coronary hemodynamics measured. Results GPR39 was identified in coronary arterioles by immunohistochemistry and in heart tissue by western blot. In-vivo, 15-HETE correlated linearly with CDP over the autoregulatory range (r 2 =0.47, p=0.0024). Apart from 6-keto PGF1 no other metabolite had any relation with CDP. Prior to administration of VC108, CBF did not change within the autoregulatory range. VC108 had no effect of systemic and pulmonary hemodynamics but increased CBF (p=0.02 versus vehicle) by decreasing coronary microvascular resistance (p=0.01 versus vehicle), indicating that GPR39 participates in control of normal coronary vascular tone. With VC108, coronary autoregulation was abolished and CBF became CDP dependent (r 2 =0.96, p=0.004). Conclusion GPR39 and its endogenous agonist 15-HETE together orchestrate coronary autoregulation when CDP is reduced. These novel findings provide a mechanism for coronary autoregulation and could direct pharmacological treatment of various coronary syndromes in humans.