Na+/H+ exchanger over-expressing mice exhibit hypertrophy and elevated response to phenylephrine

The Na+/H+ exchanger isoform 1 (NHE1) is an integral membrane protein, found in the myocardium. Recent evidence shows that NHE1 is an important contributor to myocardial ischemia/reperfusion injury and cardiac hypertrophy. NHE1 levels are upregulated in several models of heart disease. α1 adrenoreceptor agonists, which are upregulated during heart failure, enhance NHE1 activity and may potentiate the hypertrophic response and heart failure. We examined the susceptibility of NHE1 over-expressing mice to hypertrophy with or without endocrine stimulation. NHE activity of adult ventricular cardiomyocytes was elevated in the NHE1 over-expressing mice (350±12%) vs. controls (100±3.3%, P<0.05). The cell area and the HW/BW ratio were larger in the transgenic mice (111±4.7% vs. controls 100±2.6%, P<0.05 and 130.4±4.6 vs. controls 100±3.8%, P<0.05), respectively. Transgenic and control mice were then stimulated with phenylephrine (50 mg/kg/day) or PBS. The HW/BW ratio was elevated (160±7.1%, P<0.05) vs. controls (124.9±5.8%). Left ventricular cell diameter measurements were also elevated in transgenic mice (128.5±3.1, P<0.05) vs. controls (116.8±3.10). Atrial natriuretic peptide mRNA levels showed a dramatic increase in transgenic mice (555.9±7.46%, P<0.001) vs. controls (141.3±8.86%). These results demonstrate that over-expression of NHE1 is involved in the development of cardiac hypertrophy and that the hypertrophic response is accentuated in the presence of phenylephrine.