Chronic Sympathetic Hyperactivity Triggers Electrophysiological Remodeling and Disrupts Excitation-Contraction Coupling in Heart
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AbstractThe sympathetic nervous system is essential for maintenance of cardiac function via activation of post-junctional adrenergic receptors. Prolonged adrenergic receptor activation, however, has deleterious long-term effects leading to hypertrophy and the development of heart failure. Here we investigate the effect of chronic adrenergic receptors activation on excitation-contraction coupling (ECC) in ventricular cardiomyocytes from a previously characterized mouse model of chronic sympathetic hyperactivity, which are genetically deficient in the adrenoceptor α2A and α2C genes (ARDKO). When compared to wild-type (WT) cardiomyocytes, ARDKO displayed reduced fractional shortening (~33%) and slower relaxation (~20%). Furthermore, ARDKO cells exhibited several electrophysiological changes such as action potential (AP) prolongation (~50%), reduced L-type calcium channel (LCC) current (~33%), reduced outward potassium (K+) currents (~30%), and increased sodium/calcium exchanger (NCX) activity (~52%). Consistent with reduced contractility and calcium (Ca2+) currents, the cytosolic Ca2+ ([Ca2+]i) transient from ARDKO animals was smaller and decayed slower. Importantly, no changes were observed in membrane resting potential, AP amplitude, or the inward K+ current. Finally, we modified our existing cardiac ECC computational model to account for changes in the ARDKO heart. Simulations suggest that cellular changes in the ARDKO heart resulted in variable and dyssynchronous Ca2+-induced Ca2+ release therefore altering [Ca2+]i transient dynamics and reducing force generation. In conclusion, chronic sympathetic hyperactivity impairs ECC by changing the density of several ionic currents (and thus AP repolarization) causing altered Ca2+ dynamics and contractile activity. This demonstrates the important role of ECC remodeling in the cardiac dysfunction secondary to chronic sympathetic activity. Copyright 2020, The Author(s).
SponsorsThis research was supported by CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (Financial code 001), FAPEMIG - Fundação de Amparo à Pesquisa do Estado de Minas Gerais (J.S.C.), FAPESP - Fundação de Amparo à Pesquisa do Estado de São Paulo (A.S.M #2018/22830-9; J.V.J.S #2018/20777-3 and P.C.B.), CNPq - Conselho Nacional de Desenvolvimento Científico e Tecnológico (J.S.C. (Grant #312474/2017-2), P.C.B.), NIH K25 HL125762 (GSBW) and AHA #19POST34450156 (H.C.J.).
Keywordchronic sympathetic hyperactivity
Sympathetic Nervous System
Excitation Contraction Coupling
Identifier to cite or link to this itemhttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85084785586&doi=10.1038%2fs41598-020-64949-7&partnerID=40&md5=55bd0ffba192dc6f54e19f57bc09bded; http://hdl.handle.net/10713/12885