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

Abstract

BackgroundCoronary 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. MethodsWe 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. ResultsGPR39 was identified in coronary arterioles by immunohistochemistry and in heart tissue by western blot. In-vivo, 15-HETE correlated the best (r2=0.4851, p=0.0144) with CDP over the autoregulatory range using a linear mixed-effects model. Prior to administration of VC108, CBF did not change within the autoregulatory range. VC108 had no effect on 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 (r2=0.9562, p=0.0039). ConclusionGPR39 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. Clinical Perspectives What is new?The new finding from this study is that the vasoconstrictor, 15- hydroxyeicosatetraenoic acid (15-HETE), acting via the G-protein coupled receptor 39 (GPR39) participates in coronary arteriolar tone, and when perfusion pressure falls because of coronary stenosis, 15-HETE levels decrease causing vasodilation to maintain resting coronary blood flow. What are the Clinical implicationsThis mechanism, termed coronary autoregulation, causes patients with coronary artery disease to remain asymptomatic at rest until coronary stenosis is very severe. Pharmacological inhibition of GPR39 causes selective coronary vasodilation and could be used to treat coronary artery disease.