Sarcolemmal α2-adrenoceptors control protective cardiomyocyte-delimited sympathoadrenal response. (November 2016)

• Record Type: Journal Article
• Authors: Kokoz, Yuri M.; Evdokimovskii, Edward V.; Maltsev, Alexander V.; Nenov, Miroslav N.; Nakipova, Olga V.; Averin, Alexey S.; Pimenov, Oleg Yu.; Teplov, Ilia Y.; Berezhnov, Alexey V.; Reyes, Santiago; Alekseev, Alexey E.
• Is Part Of: Journal of molecular and cellular cardiology. Volume 100(2016:Nov.)
• Page Start: 9
• Page End: 20
• Publication Date: 2016-11
• Subjects: 7NI 7-nitroindazole, NOS inhibitor -- 8Br-cGMP 8-bromoguanosine 3′, 5′-cyclic monophosphate, membrane permeable cGMP analog -- Akt/PKB Akt or protein kinase B, serine/threonine-specific protein kinase -- DAF-FM 4-amino-5-methylamino-2′, 7′-Difluorofluorescein -- eNOS endothelial NO synthase -- ICaL voltage-gated L-type Ca2+ current -- NE norepinephrine -- NO nitric oxide -- PDE phosphodiesterase -- PKA cAMP-dependent protein kinase -- PKG cGMP-dependent protein kinase -- PP1 and PP2A protein phosphatases 1 and 2A, respectively -- SD Sprague-Dawley rats -- SERCA sarco/endoplasmic reticulum Ca2+ ATPase -- sGC soluble guanylate cyclase -- SHR spontaneously hypertensive rats -- SNAP S-nitroso-N-acetyl-D, L-penicillamine, NO donor -- SNP Sodium nitroprusside, NO donor -- SR sarcoplasmic reticulum; Protein phosphatase -- Intracellular Ca2+ -- Adrenergic stress -- Norepinephrine -- Spontaneously hypertensive rats (SHR) -- Cardiac hypertrophy -- Heart failure; Cardiology -- Periodicals; Heart Diseases -- Periodicals; Molecular Biology -- Periodicals; Cardiologie -- Périodiques; Cardiology; Electronic journals; Periodicals; 616.12
• DOI: 10.1016/j.yjmcc.2016.09.006
• Languages: English
• ISSNs: 0022-2828

Abstract

Abstract: Sustained cardiac adrenergic stimulation has been implicated in the development of heart failure and ventricular dysrhythmia. Conventionally, α2 adrenoceptors (α2-AR) have been assigned to a sympathetic short-loop feedback aimed at attenuating catecholamine release. We have recently revealed the expression of α2-AR in the sarcolemma of cardiomyocytes and identified the ability of α2-AR signaling to suppress spontaneous Ca 2+ transients through nitric oxide (NO) dependent pathways. Herein, patch-clamp measurements and serine/threonine phosphatase assay revealed that, in isolated rat cardiomyocytes, activation of α2-AR suppressed L-type Ca 2+ current ( I CaL ) via stimulation of NO synthesis and protein kinase G- (PKG) dependent activation of phosphatase reactions, counteracting isoproterenol-induced β-adrenergic activation. Under stimulation with norepinephrine (NE), an agonist of β- and α-adrenoceptors, the α2-AR antagonist yohimbine substantially elevated I CaL at NE levels > 10 nM. Concomitantly, yohimbine potentiated triggered intracellular Ca 2+ dynamics and contractility of cardiac papillary muscles. Therefore, in addition to the α2-AR-mediated feedback suppression of sympathetic and adrenal catecholamine release, α2-AR in cardiomyocytes can govern a previously unrecognized local cardiomyocyte-delimited stress-reactive signaling pathway. We suggest that such aberrant α2-AR signaling may contribute to the development of cardiomyopathy under sustained sympathetic drive. Indeed, in cardiomyocytes of spontaneously hypertensive rats (SHR), an established model of cardiac hypertrophy, α2-AR signaling was dramatically reduced despite increased α2-AR mRNA levels compared to normal cardiomyocytes. Thus, targeting α2-AR signaling mechanisms in cardiomyocytes may find implications in medical strategies against maladaptive cardiac remodeling associated with chronic sympathoadrenal stimulation. Highlights: α2-AR in cardiomyocytes suppress voltage-gated L-type Ca 2 + channels ( I CaL ). NO-dependent α2-AR signaling suppresses I CaL via cGPM - PKG-dependent routes. α2-AR signaling alters kinase-phosphatase balance opposing β-adrenergic stimulation. α2-AR control [Ca 2 + ]in and contractility outcomes during catecholamine surge. aberrant α2-AR signaling in SHR cardiomyocytes may be linked to cardiac hypertrophy.