Elevated Myocardial Na+/H+ Exchanger Elicits the Expression of Genes that Lead to Cardiac Hypertrophy. Mus musculus

In myocardial disease, elevated expression and activity of Na+/H+ exchanger isoform 1 (NHE1) is detrimental. To better understand the involvement of NHE1, transgenic mice with elevated heart-specific NHE1 expression were studied. N-line mice expressed wild-type NHE1 and K-line mice expressed activated NHE1. Cardiac morphology, interstitial fibrosis and cardiac function were examined by histological staining and echocardiography. Differences in gene expression between the N- or K-line and non-transgenic littermates were probed using genechips. We found that NHE1 K-line hearts (but not N-line) developed hypertrophy, including elevated heart weight to body weight and increased cross sectional area of the cardiomyocytes, interstitial fibrosis, as well as depressed cardiac function. N-line transgenic hearts had modest changes in gene expression (50 up-regulations and 99 down-regulations, P<0.05), whereas K-line hearts had a very strong transcriptional response (640 up-regulations and 677 down-regulations, P<0.05). In addition, the magnitude of expression alterations was much higher in K-line than in N-line transgenic mice. The most significant changes in gene expression were involved in cardiac hypertrophy, cardiac necrosis/cell death and cardiac infarction. Secreted phosphoprotein 1 signaling pathways were up-regulated while peroxisome proliferative activated receptor gamma signaling was down-regulated in K-line mice. Our study shows that expression of activated NHE1 elicits specific pathways of gene activation in the myocardium that lead to cardiac hypertrophy, cell death and infarction. Overall design: Alterations on gene expression profiles were determined in the hearts of transgenic mice carrying either a wild-type NHE1 gene (N-line) or a constitutively active NHE1 mutant gene (K-line).