Journal of the American Heart Association · 2026
15-Hydroxyeicosatetraenoic Acid and G-Protein Coupled Receptor 39 Together Orchestrate Coronary Autoregulation: A Comprehensive Metabolomic Analysis.
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Le D Elizabeth, Kajimoto Masaki, Zhao Yan, Methner Carmen, Cao Zhiping, Minnier Jessica, Cianciulli Agostino, Semeraro Teresa, Trist Iuni Margaret Laura, Franchi Jessica, Marcheselli Chiara, Parazzoli Alberto, Micheli Fabrizio, Kaul Sanjiv
Аннотация
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 (CDPs). Despite being vital for survival, the mechanism of coronary autoregulation is unknown. We hypothesized that G-protein coupled receptor 39 (GPR39), present in vascular smooth muscle cells, together with its endogenous agonist 15-hydroxyeicosatetraenoic acid 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-hydroxyeicosatetraenoic acid correlated the best (r2=0.56, P=0.0003) with CDP over the autoregulatory range using a linear mixed-effects model. Before 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).
CONCLUSIONS: GPR39 and its endogenous agonist 15-hydroxyeicosatetraenoic acid 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.
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-hydroxyeicosatetraenoic acid correlated the best (r2=0.56, P=0.0003) with CDP over the autoregulatory range using a linear mixed-effects model. Before 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).
CONCLUSIONS: GPR39 and its endogenous agonist 15-hydroxyeicosatetraenoic acid 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.