Sarcolemmal α2-adrenoceptors control protective cardiomyocyte-delimited sympathoadrenal response

Yuri M. Kokoz, Edward V. Evdokimovskii, Alexander V. Maltsev, Miroslav N. Nenov, Olga V. Nakipova, Alexey S. Averin, Oleg Yu Pimenov, Ilia Y. Teplov, Alexey V. Berezhnov, Santiago Reyes, Alexey E. Alekseev

Research output: Contribution to journalArticle

9 Citations (Scopus)

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 Ca2+ 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 Ca2+ current (ICaL) 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 ICaL at NE levels > 10 nM. Concomitantly, yohimbine potentiated triggered intracellular Ca2+ 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.

Original languageEnglish (US)
Pages (from-to)9-20
Number of pages12
JournalJournal of Molecular and Cellular Cardiology
Volume100
DOIs
StatePublished - Nov 1 2016

Fingerprint

Cardiac Myocytes
Adrenergic Receptors
Yohimbine
Adrenergic Agents
Catecholamines
Norepinephrine
Nitric Oxide
Cyclic GMP-Dependent Protein Kinases
Sarcolemma
Papillary Muscles
Phosphoprotein Phosphatases
Cardiomegaly
Inbred SHR Rats
Cardiomyopathies
Isoproterenol
Phosphoric Monoester Hydrolases
Myocardium
Heart Failure
Messenger RNA

Keywords

  • Cardiac hypertrophy
  • Heart failure
  • Intracellular Ca
  • Norepinephrine
  • Protein phosphatase
  • Spontaneously hypertensive rats (SHR)
  •  Adrenergic stress

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

Cite this

Kokoz, Y. M., Evdokimovskii, E. V., Maltsev, A. V., Nenov, M. N., Nakipova, O. V., Averin, A. S., ... Alekseev, A. E. (2016). Sarcolemmal α2-adrenoceptors control protective cardiomyocyte-delimited sympathoadrenal response. Journal of Molecular and Cellular Cardiology, 100, 9-20. https://doi.org/10.1016/j.yjmcc.2016.09.006

Sarcolemmal α2-adrenoceptors control protective cardiomyocyte-delimited sympathoadrenal response. / 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.

In: Journal of Molecular and Cellular Cardiology, Vol. 100, 01.11.2016, p. 9-20.

Research output: Contribution to journalArticle

Kokoz, YM, Evdokimovskii, EV, Maltsev, AV, Nenov, MN, Nakipova, OV, Averin, AS, Pimenov, OY, Teplov, IY, Berezhnov, AV, Reyes, S & Alekseev, AE 2016, 'Sarcolemmal α2-adrenoceptors control protective cardiomyocyte-delimited sympathoadrenal response', Journal of Molecular and Cellular Cardiology, vol. 100, pp. 9-20. https://doi.org/10.1016/j.yjmcc.2016.09.006
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. / Sarcolemmal α2-adrenoceptors control protective cardiomyocyte-delimited sympathoadrenal response. In: Journal of Molecular and Cellular Cardiology. 2016 ; Vol. 100. pp. 9-20.
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AU - Nenov, Miroslav N.

AU - Nakipova, Olga V.

AU - Averin, Alexey S.

AU - Pimenov, Oleg Yu

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