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Cellini, A; Höfler, D; Arias-Loza, PA; Bandleon, S; Langsenlehner, T; Kohlhaas, M; Maack, C; Bauer, WR; Eder-Negrin, P.
The α2-isoform of the Na+/K+-ATPase protects against pathological remodeling and β-adrenergic desensitization after myocardial infarction.
Am J Physiol Heart Circ Physiol. 2021; 321(4):H650-H662 Doi: 10.1152/ajpheart.00808.2020
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Langsenlehner Tanja

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The role of the Na+/K+-ATPase (NKA) in heart failure associated with myocardial infarction (MI) is poorly understood. The elucidation of its precise function is hampered by the existence of two catalytic NKA isoforms (NKA-α1 and NKA-α2). Our aim was to analyze the effects of an increased NKA-α2 expression on functional deterioration and remodeling during long-term MI treatment in mice and its impact on Ca2+ handling and inotropy of the failing heart. Wild-type (WT) and NKA-α2 transgenic (TG) mice (TG-α2) with a cardiac-specific overexpression of NKA-α2 were subjected to MI injury for 8 wk. As examined by echocardiography, gravimetry, and histology, TG-α2 mice were protected from functional deterioration and adverse cardiac remodeling. Contractility and Ca2+ transients (Fura 2-AM) in cardiomyocytes from MI-treated TG-α2 animals showed reduced Ca2+ amplitudes during pacing or after caffeine application. Ca2+ efflux in cardiomyocytes from TG-α2 mice was accelerated and diastolic Ca2+ levels were decreased. Based on these alterations, sarcomeres exhibited an enhanced sensitization and thus increased contractility. After the acute stimulation with the β-adrenergic agonist isoproterenol (ISO), cardiomyocytes from MI-treated TG-α2 mice responded with increased sarcomere shortenings and Ca2+ peak amplitudes. This positive inotropic response was absent in cardiomyocytes from WT-MI animals. Cardiomyocytes with NKA-α2 as predominant isoform minimize Ca2+ cycling but respond to β-adrenergic stimulation more efficiently during chronic cardiac stress. These mechanisms might improve the β-adrenergic reserve and contribute to functional preservation in heart failure.NEW & NOTEWORTHY Reduced systolic and diastolic calcium levels in cardiomyocytes from NKA-α2 transgenic mice minimize the desensitization of the β-adrenergic signaling system. These effects result in an improved β-adrenergic reserve and prevent functional deterioration and cardiac remodeling.
Find related publications in this database (using NLM MeSH Indexing)
Adrenergic beta-Agonists - pharmacology
Animals - administration & dosage
Calcium - metabolism
Calcium Signaling - drug effects
Disease Models, Animal - administration & dosage
Female - administration & dosage
Heart Failure - enzymology, genetics, pathology, physiopathology
Male - administration & dosage
Mice, Transgenic - administration & dosage
Myocardial Contraction - drug effects
Myocardial Infarction - enzymology, genetics, pathology, physiopathology
Myocardial Reperfusion Injury - enzymology, genetics, pathology, physiopathology
Myocytes, Cardiac - drug effects, enzymology, pathology
Receptors, Adrenergic, beta - drug effects, metabolism
Sodium-Potassium-Exchanging ATPase - genetics, metabolism
Ventricular Remodeling - drug effects

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