Journal
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY
Volume 307, Issue 11, Pages C1050-C1057Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpcell.00127.2014
Keywords
long QT syndrome; SERCA2a; hormones; cardiomyocytes; neonate
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Funding
- National Heart, Lung, and Blood Institute [5R01 HL-093205-04, 1R01 HL-110791-01A1, 5R01 HL-096669, 5T32 HL-094300]
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL110791, R01HL093205, T32HL094300, R01HL096669] Funding Source: NIH RePORTER
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We recently showed that progesterone treatment abolished arrhythmias and sudden cardiac death in a transgenic rabbit model of long QT syndrome type 2 (LQT2). Moreover, levels of cardiac sarco(endo) plasmic reticulum Ca2+-ATPase type 2a (SERCa2a) were upregulated in LQT2 heart extracts. We hypothesized that progesterone treatment upregulated SERCa2+a expression, thereby reducing Ca2+-dependent arrhythmias in LQT2 rabbits. We therefore investigated the effect of progesterone on SERCa2a regulation in isolated cardiomyocytes. Cardiomyocytes from neonatal (3- to 5-day-old) rabbits were isolated, cultured, and treated with progesterone and other pharmacological agents. Immunoblotting was performed on total cell lysates and sarcoplasmic reticulum-enriched membrane fractions for protein abundance, and mRNA transcripts were quantified using real-time PCR. The effect of progesterone on baseline Ca2+ transients and Ca2+ clearance was determined using digital imaging. Progesterone treatment increased the total pool of SERCa2a protein by slowing its degradation. Using various pharmacological inhibitors of degradation pathways, we showed that progesterone-associated degradation of SERCa2a involves ubiquitination, and progesterone significantly decreases the levels of ubiquitin-tagged SERCa2a polypeptides. Our digital imaging data revealed that progesterone significantly shortened the decay and duration of Ca2+ transients. Progesterone treatment increases protein levels and activity of SERCa2a. Progesterone stabilizes SERCa2a, in part, by decreasing the ubiquitination level of SERCa2a polypeptides.
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