Nogo-A Modulates Calcium Handling and Contractility in Cardiomyocytes

Abstract

Key features in the progression from left ventricular hypertrophy to heart failure include the dysregulation of cardiomyocyte Ca2+ handling and the impairment of contractile function. Knockdown of Nogo-A has previously been shown to inhibit hypoxia/reoxygenation-induced apoptosis in cardiomyocytes in part by preventing impairment of intracellular Ca2+ regulation. In this study, we determined whether altering Nogo-A expression can affect cardiomyocyte Ca2+ handling and contractility in non-stressed cardiomyocytes. Compared to control, knockdown of Nogo-A in neonatal rat ventricular myocytes (NRVMs) significantly increased the amplitude of [Ca2+]i transients, increased SR load, and decreased the time constant of [Ca2+]i decay (tau) evoked by electrical stimulation. Diastolic [Ca2+]i, time to peak, and [Ca2+]i decay of caffeine-induced Ca2+ release from the SR were not affected by Nogo-A knockdown. Conversely, over-expression of Nogo-A in adult rabbit cardiomyocytes significantly decreased the amplitude of [Ca2+]i transients, decreased SR load, and increased the time constant of [Ca2+]i decay. Diastolic [Ca2+]i, time to peak, and [Ca2+]i decay of caffeine-induced Ca2+ release from the SR were not affected by Nogo-A overexpression. In addition to the impairment of Ca2+ handling, Nogo-A over-expression significantly decreased sarcomere length (SL) shortening, increased the time to 90% relaxation (TR90), and decreased relaxation velocity. Contraction velocity was not affected by Nogo-A over-expression. Overall, alteration of Nogo-A levels affects cardiomyocyte Ca2+ handling and contractility, primarily by modulating Ca2+ reuptake into the SR. Together, these data indicate that Nogo-A may serve as a potential therapeutic target in the treatment or prevention of heart failure.