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₂-Adrenergic Signaling in Human Heart: Shift from the Cyclic AMP to the Arachidonic Acid Pathway

Institut National de la Santé et de la Recherche Médicale (INSERM) Unité 581 (C.P., S.L., A.P., C.F., N.D., S.M., A.A. F.P.), Service Anesthésie-Réanimation (N.B., P.D.), Unité Evaluation-Etudes (F.R.-T.), and Service de Chirurgie Cardiaque (R.H., D.L.), Hôpital Henri Mondor, Créteil, France; INSERM Unité 533, Hôtel Dieu, Nantes, France (C.G.); Centre National de la Recherche Scientifique-ESA 8078, Hôpital Marie-Lannelongue, Le Plessis-Robinson, France (C.R.M.)

We have recently established that enhancement of intracellular calcium cycling and contraction in response to ₂-adrenergic receptor (₂-AR) stimulation exclusively relies on the activation of the cytosolic phospholipase A₂ (cPLA₂) and arachidonic acid production, via a pertussis toxin-sensitive G protein (possibly Gi), in embryonic chick cardiomyocytes. We aimed to investigate the relevance of the ₂-AR/Gi/cPLA₂ pathway in the human myocardium. In left ventricular biopsies obtained from explanted hearts, ₂-AR stimulation exerted either an inhibition of cPLA₂ that was insensitive to pertussis toxin (PTX) treatment, or an activation of cPLA₂, sensitive to PTX treatment. In right atrial appendages from patients who were undergoing open heart surgery, we demonstrated that ₂-AR-induced activation of cPLA₂ was favored in situations of altered ₁-AR and/or ₂-AR/adenylyl cyclase (AC) stimulations. Alterations were characterized by an increase in EC₅₀value of norepinephrine and a decrease in the maximal AC activation in response to zinterol, respectively. Quantitative reverse transcription-polymerase chain reaction analyses highlighted a positive correlation between the expression of AC5 and AC6 mRNAs in human cardiac atria, which suggested that functional alterations in AC responses were unlikely to be related to changes in the AC5/AC6 mRNA ratio. In addition, the shift from the cyclic AMP to the arachidonic acid pathway was not supported at the transcriptional level by opposite regulation of AC and cPLA₂mRNAs expression. This study gives the first evidence of the recruitment of cPLA₂by ₂-ARs in the human heart and suggests that the Gi/cPLA₂pathway could substitute for a deficient Gs/AC pathway in mediating ₂-AR responses.

Address correspondence to: Prof. C. Pavoine, INSERM Unité 581, Hôpital Henri Mondor, 94010 Créteil, France. E-mail: pavoine{at}im3.inserm.fr

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