title: Antiapolipoprotein A-1 IgG chronotropic effects require nongenomic action of aldosterone on L-type calcium channels.
abstract: Autoantibodies to apolipoprotein A-1 (antiapoA-1 IgG) have been shown to be associated with higher resting heart rate and morbidity in myocardial infarction patients and to behave as a chronotropic agent in the presence of aldosterone on isolated neonatal rat ventricular cardiomyocytes (NRVC). We aimed at identifying the pathways accounting for this aldosterone-dependent antiapoA-1 IgG-positive chronotropic effect on NRVC. The rate of regular spontaneous contractions was determined on NRVC in the presence of different steroid hormones and antagonists. AntiapoA-1 IgG chronotropic response was maximal within 20 min and observed only in aldosterone-pretreated cells but not in those exposed to other steroids. The positive antiapoA-1 IgG chronotropic effect was already significant after 5 min aldosterone preincubation, was dependent on 3-kinase and protein kinase A activities, was not inhibited by actinomycin D, and was fully abrogated by eplerenone (but not by spironolactone), demonstrating the dependence on a nongenomic action of aldosterone elicited through the mineralocorticoid receptor (MR). Under oxidative conditions (but not under normal redox state), corticosterone mimicked the permissive action of aldosterone on the antiapoA-1 IgG chronotropic response. Pharmacological and patch-clamp studies identified L-type calcium channels as crucial effectors of antiapoA-1 IgG chronotropic action, involving two converging pathways that increase the channel activity. The first one involves the rapid, nongenomic activation of the phosphatidylinositol 3-kinase enzyme by MR, and the second one requires a constitutive basal protein kinase A activity. In conclusion, our results indicate that, on NRVC, the aldosterone-dependent chronotropic effects of antiapoA-1 IgG involve the nongenomic activation of L-type calcium channels.
authors.affiliation: Service of Endocrinology and Diabetology, Department of Internal Medicine, Geneva University Hospitals, Geneva, Switzerland.
authors.forename: Michel F
authors.initials: MF
authors.lastname: Rossier
authors.forename: Sabrina
authors.initials: S
authors.lastname: Pagano
authors.forename: Magaly
authors.initials: M
authors.lastname: Python
authors.forename: Andres D
authors.initials: AD
authors.lastname: Maturana
authors.forename: Richard W
authors.initials: RW
authors.lastname: James
authors.forename: François
authors.initials: F
authors.lastname: Mach
authors.forename: Pascale
authors.initials: P
authors.lastname: Roux-Lombard
authors.forename: Nicolas
authors.initials: N
authors.lastname: Vuilleumier
mesh_terms: D000450:Aldosterone / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D016632:Apolipoprotein A-I / Q000737:chemistry*; D020746:Calcium Channels, L-Type / Q000737:chemistry*; D002478:Cells, Cultured; D003609:Dactinomycin / Q000494:pharmacology; D004594:Electrophysiology / Q000379:methods; D000077545:Eplerenone; D007074:Immunoglobulin G / Q000737:chemistry*; D032383:Myocytes, Cardiac / Q000166:cytology; D010084:Oxidation-Reduction; D010100:Oxygen / Q000737:chemistry; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018161:Receptors, Mineralocorticoid / Q000378:metabolism; D013148:Spironolactone / Q000031:analogs & derivatives / Q000494:pharmacology; D013997:Time Factors
chemical_list: D016632:Apolipoprotein A-I; D020746:Calcium Channels, L-Type; D007074:Immunoglobulin G; D018161:Receptors, Mineralocorticoid; D003609:Dactinomycin; D013148:Spironolactone; D000450:Aldosterone; D000077545:Eplerenone; D019869:Phosphatidylinositol 3-Kinases; D010100:Oxygen