The sarco(endo)plasmic reticulum Ca2+-ATPase gene is regulated at the transcriptional level during compensated left ventricular hypertrophy in the rat

Abstract

In mammalian myocardium, relaxation is mainly triggered by the reuptake of calcium form the cytosol to the lumen of the sarcoplasmic reticulum (SR) through the cardiac isoform of the sarco(endo)plasmic reticulum calcium ATPase, SERCA2a. Relaxation abnormalities related to deficient SR Ca2+-uptake have been identified in human heart failure and in animal models of cardiac hypertrophy and failure. These alterations have been associated with a reduction in SERCA2a activity and in steady-state SERCA2a protein and mRNA levels. As a first step in the analysis of the mechanisms responsible for this reduction, we have studied a possible down-regulation of the SERCA2 gene transcription during left ventricular hypertrophy (LVH) induced by constriction of the ascending aorta in the rat. Quantifications of the mRNA levels demonstrated no alteration, compared to sham-operated rats, at 5 d after imposition of the pressure overload, whereas a significant decrease was observed at 11 d. Transcription in-vitro experiments (cardiac nuclear run-on assays) performed in isolated cardiomyocytes nuclei showed no changes at 5 d and a 37% reduction of the SERCA2 gene transcription at 11 d. These results strongly suggest that SERCA2 gene expression down-regulation during cardiac hypertrophy occurs, at least in part, at the level of the transcription.