oa In Vivo Characterization Of A New Mouse Model Expressing The Na+/h+ Exchanger Isoform 1 Of Dilated Cardiomyopathy

Rational: Heart failure is a common, costly, and frequently fatal disease. One in three cases of heart failure is due to dilated cardiomyopathy. NHE1 expression and activity are increased in this cardiac defect. We have previously shown that elevated activity of NHE1 in the cardiomyocytes induced cardiac hypertrophy in transgenic mice. However, it protected the myocardium following ischemia/reperfusion. This overexpression of active NHE1 elicited modulation of gene expression in cardiomyocytes including an up regulation of myocardial osteopontin (OPN) expression and a decrease of peroxisome proliferator-activated receptor (PPAR)γ. Since transgenic mice phenotype is very often influenced by the integration position of the transgene, we decide to create new transgenic mice to ascertain our previous data and to test the role of modulated genes. Method and results: We have created 5 new mouse lines overexpressing a constitutively active form of NHE1 specifically in cardiomyocytes (KNHE1+). We have evaluated by echocardiography the cardiac phenotypes and function of two of these new mouse lines. Then heart were harvested and submitted to histological, immunohistological and QRT-PCR analysis. Our data showed that in the both KNHE1 studied lines, a number of mice demonstrated heart remodeling identified by a significant decrease in diastolic interventricular septal (IVSd) and diastolic left ventricular posterior wall (LVPW) thickness and an increased diastolic left ventricular internal dimension (LVIDd) (see table 1). Moreover these hearts demonstrated impaired function with a decreased fraction shortening (<21 % vs 31% in wild type mouse) and ejection fraction. However, the proportion of 12 weeks old mice demonstrating this defect is different in both lines 13% (3/24) in line #4 and 58% (11/19) in line#1 vs 0% (0/37). ANP and BNP up regulation in line #1 confirmed heart suffering. Current experiment is designed to perform a longitudinal study examining evolution of these proportions with the age of the animals. Conclusions: We have developed an interesting comparative model of active NHE1 transgenic mouse lines with low and high rate dilated cardiomyopathy identifying evidence of early and late mechanisms. Further studies will be conducted to evaluate the phenotypes of the other mouse lines and the mechanism by which these changes are occuring.