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NOX Inhibition Improves β-Adrenergic Stimulated Contractility and Intracellular Calcium Handling in the Aged Rat Heart.
International Journal of Molecular Sciences 2018 August 16
Cardiac aging is characterized by alterations in contractility and intracellular calcium ([Ca2+ ] i ) homeostasis. It has been suggested that oxidative stress may be involved in this process. We and others have reported that in cardiomyopathies the NADPH oxidase (NOX)-derived superoxide is increased, with a negative impact on [Ca2+ ] i and contractility. We tested the hypothesis that in the aged heart, [Ca2+ ] i handling and contractility are disturbed by NOX-derived superoxide. For this we used adults (≈5 month-old) and aged (20⁻24 month-old) rats. Contractility was evaluated in isolated hearts, challenged with isoproterenol. To assess [Ca2+ ] i , isolated cardiac myocytes were field-stimulated and [Ca2+ ] i was monitored with fura-2. Cardiac concentration-response to isoproterenol was depressed in aged compared to adults hearts ( p < 0.005), but was restored by NOX inhibitors apocynin and VAS2870. In isolated cardiomyocytes, apocynin increased the amplitude of [Ca2+ ] i in aged myocytes ( p < 0.05). Time-50 [Ca2+ ] i decay was increased in aged myocytes ( p < 0.05) and reduced towards normal by NOX inhibition. In addition, we found that myofilaments Ca2+ sensitivity was reduced in aged myocytes ( p < 0.05), and was further reduced by apocynin. NOX2 expression along with NADPH oxidase activity was increased in aged hearts. Phospholamban phosphorylation (Ser16/Thr17) after isoproterenol treatment was reduced in aged hearts compared to adults and was restored by apocynin treatment ( p < 0.05). In conclusion, β-adrenergic-induced contractility was depressed in aged hearts, and NOX inhibition restored back to normal. Moreover, altered Ca2+ handling in aged myocytes was also improved by NOX inhibition. These results suggest a NOX-dependent effect in aged myocytes at the level of Ca2+ handling proteins and myofilaments.
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