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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE19819 | GEO | 2010/05/17

SECONDARY ACCESSION(S): PRJNA122143

REPOSITORIES: GEO

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Project description:Muscle ring finger-1 (MuRF1) is a muscle-specific protein implicated in the regulation of cardiac myocyte size and contractility. MuRF2, a closely related family member, redundantly interacts with protein substrates, and hetero-dimerizes with MuRF1. Mice lacking either MuRF1 or MuRF2 are phenotypically normal whereas mice lacking both proteins develop a spontaneous cardiac and skeletal muscle hypertrophy indicating cooperative control of muscle mass by MuRF1 and MuRF2. In order to identify the role that MuRF1 plays in regulating cardiac hypertrophy in vivo, we created transgenic mice expressing increased amounts of cardiac MuRF1. Adult MuRF1 transgenic (Tg+) hearts exhibited a non-progressive thinning of the left ventricular wall and a concomitant decrease in cardiac function. Experimental induction of cardiac hypertrophy by trans-aortic constriction (TAC) induced rapid failure of MuRF1 Tg+ hearts. Microarray analysis identified that the levels of genes associated with metabolism (and in particular mitochondrial processes) were significantly altered in MuRF1 Tg+ hearts, both at baseline and during the development of cardiac hypertrophy. Surprisingly, ATP levels in MuRF1 Tg+ mice did not differ from wild type mice despite the depressed contractility following TAC. To explain this discrepancy between the ongoing heart failure and maintained ATP levels in MuRF1 Tg+ hearts, we compared the level and activity of creatine kinase (CK) between wild type and MuRF1 Tg+ hearts. Although mCK and CK-M/B protein levels were unaffected in MuRF1 Tg+ hearts, total CK activity was significantly inhibited. We conclude that MuRF1’s inhibition of CK activity leads to increased susceptibility to heart failure following TAC, demonstrating for the first time that MuRF1 regulates cardiac energetics in vivo. Keywords: Genetic modification, physiological manipulation. Three-condition experiment, MuRF1 Tg+ vs. WT mice. Biological replicates: 4 WT baseline, 3 MuRF1 Tg+ baseline, cardiac overpressure hypertrophy induced by trans-aortic banding at 1 week (3 WT, 3 MurF Tg) and 4 weeks (3 WT, 3 MurF Tg), hearts harvested. One replicate per array.

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

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