?-adrenergic activation may promote myosin light chain kinase degradation through calpain in pressure overload-induced cardiac hypertrophy : ?-adrenergic activation results in MLCK degradation - 28/08/20
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Graphical abstract |
Highlights |
• | β-blocker reverses the decrease in MLCK and increase in calpain in pressure overload-induced cardiac hypertrophy. |
• | β-receptor activation reduces MLCK and increases calpain in cardiomyocytes. |
• | Inhibition of calpain reverses the isoproterenol-induced MLCK reduction and cardiomyocyte hypertrophy. |
• | Calpain degrades MLCK in vitro. |
Abstract |
Background |
β-adrenergic activation is able to exacerbate cardiac hypertrophy. Myosin light chain kinase (MLCK) and its phosphorylated substrate, phospho-myosin light chain 2 (p-MLC2), play vital roles in regulating cardiac hypertrophy. However, it is not yet clear whether there is a relationship between β-adrenergic activation and MLCK in the progression of cardiac hypertrophy. Therefore, we explored this relationship and the underlying mechanisms in this work.
Methods |
Cardiac hypertrophy and cardiomyocyte hypertrophy were induced by pressure overload and isoproterenol (ISO) stimulation, respectively. Echocardiography, histological analysis, immunofluorescence and qRT-PCR were used to confirm the successful establishment of the models. A β-blocker (metoprolol) and a calpain inhibitor (calpeptin) were administered to inhibit β-adrenergic activity in rats and calpain in cardiomyocytes, respectively. The protein expression levels of MLCK, myosin light chain 2 (MLC2), p-MLC2, myosin phosphatase 2 (MYPT2), calmodulin (CaM) and calpain were measured using western blotting. A cleavage assay was performed to assess the degradation of recombinant human MLCK by recombinant human calpain.
Results |
The β-blocker alleviated cardiac hypertrophy and dysfunction, increased MLCK and MLC2 phosphorylation and decreased calpain expression in pressure overload-induced cardiac hypertrophy. Additionally, the calpain inhibitor calpeptin attenuated cardiomyocyte hypertrophy, upregulated MLCK and p-MLC2 and reduced MLCK degradation in ISO-induced cardiomyocyte hypertrophy. Recombinant human calpain degraded recombinant human MLCK in vitro in concentration- and time-dependent manners, and this degradation was inhibited by the calpain inhibitor calpeptin.
Conclusion |
Our study suggested that β-adrenergic activation may promote the degradation of MLCK through calpain in pressure overload-induced cardiac hypertrophy.
El texto completo de este artículo está disponible en PDF.Keywords : Cardiac hypertrophy, β-adrenergic activity, Myosin light chain kinase, Calpain
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Vol 129
Artículo 110438- septembre 2020 Regresar al númeroBienvenido a EM-consulte, la referencia de los profesionales de la salud.
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