Abstract
Intracellular Ca2+ overload secondary to chronic hemodynamic stimuli promotes the recruitment of Ca2+-dependent signaling implicated in cardiomyocyte hypertrophy. The present study tested the hypothesis that sympathetic-mediated hypertrophy of neonatal rat ventricular cardiomyocytes (NRVMs) translated to an increase in calcium influx secondary to the upregulation of CaV1.2 channel subunits. Confocal imaging of norepinephrine (NE)-treated NRVMs revealed a hypertrophic response compared to untreated NRVMs. L-type CaV1.2 peak current density was increased 4-fold following a 24-h stimulation with NE. NE-treated NRVMs exhibited a significant upregulation of CaVα2δ1 and CaVβ3 protein levels without significant changes of CaVα1C and CaVβ2 protein levels. Pre-treatment with the β1-blocker metoprolol failed to inhibit hypertrophy or CaVβ3 upregulation whereas CaVα2δ1 protein levels were significantly reduced. NE promoted the phosphorylation of ERK 1/2, and the response was attenuated by the β1-blocker. U0126 pre-treatment suppressed NE-induced ERK1/2 phosphorylation but failed to attenuate hypertrophy. U0126 inhibition of ERK1/2 phosphorylation prevented NE-mediated upregulation of CaVα2δ1, whereas CaVβ3 protein levels remained elevated. Thus, β1-adrenergic receptor-mediated recruitment of the ERK1/2 plays a seminal role in the upregulation of CaVα2δ1 in NRVMs independent of the concomitant hypertrophic response. However, the upregulation of CaVβ3 protein levels may be directly dependent on the hypertrophic response of NRVMs.
Highlights
Normal intracellular Ca2+ cycling and homeostasis are required for cardiac excitability, contractility, and gene expression [1,2]
As compared to untreated neonatal rat ventricular cardiomyocytes (NRVMs), a significant hypertrophic response as depicted by the increase in cell surface area was detected after a 24-h stimulation with NE, and hypertrophy persisted
Numerous in vitro and in vivo studies have delineated the role of calcium-dependent signaling events linking various stimuli to ventricular cardiomyocyte hypertrophy [29–31]
Summary
Normal intracellular Ca2+ cycling and homeostasis are required for cardiac excitability, contractility, and gene expression [1,2]. Several studies have reported that intracellular calcium overload secondary to a sustained hemodynamic stimulus contributed to the development of cardiac hypertrophy via recruitment of the nuclear factor of activated T cells (NFAT) pathway and calmodulin kinase-dependent signaling events [3–5]. Cardiac hypertrophy is an adaptive mechanism secondary to a sustained chronic hemodynamic overload [6–8]. In response to elevated mean arterial pressure, the heart develops a concentric pattern of cardiac hypertrophy [6–8]. New sarcomeres are added in a parallel fashion leading to an increase in the width of individual ventricular cardiomyocytes [6–8]. The latter response translates to increased ventricular wall thickness and reduced chamber diameter [6–8]
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