Abstract
Background: In hypertrophied cardiac myocytes VSOAC s become constitutively activated. In this study, we used a murine line targeting ClC-3, a gene encoding native VSOACs in the heart, to explore the molecular mechanism for the potential role of VSOACs in pressure overload-induced myocardial hypertrophy and the progression to heart failure. Methods: A pressure overload model through a minimally invasive transverse aortic banding (MTAB) at the suprasternal notch level was established in age-matched ClCn3 −/− mice and their wild-type (WT) littermates. Echocardiography, whole-cell voltage-clamp technique, microarray (Affymetrix chips) and proteomic analysis were used to examine the changes in cardiac phenotype and in gene and protein expression profiles. Results: In 13/16 (81%) left ventricular myocytes isolated from WT mice subjected to MTAB for 5 weeks (wks) a large outwardly rectifying Cl − current was activated under isotonic conditions. Hypotonic cell swelling caused no changes in the current while it was significantly inhibited by hypertonic cell shrinkage or by intracellular dialysis of anti-ClC-3 antibody. The increase in wall thickness (myocardial hypertrophy) peaked significantly faster in ClCn3 −/− mice (<1 wk) than in WT mice (>4 wks). After MTAB the hypertrophied changes remained at a similar level for >10 wks in WT mice, but heart failure accompanied by a significant decrease in wall thickness and increase in chamber dimensions developed in <6 wks in ClCn3 −/− mice. Microarray and proteomic analyses in WT and ClCn3 −/− mouse myocardium pre and post MTAB for 1 and 5 wks revealed complex changes in gene and protein expression profiles involving not only ion channels but also cytoskeleton and signal transducer proteins. Conclusion: The constitutively activated VSOACs in hypertrophied heart may be due to ClC-3. Activation of VSOACs may delay the progression from myocardial hypertrophy to heart failure.
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