Left ventricular dysfunction in murine models of heart failure and in failing human heart is associated with a selective decrease in the expression of caveolin-3.
BACKGROUND: Caveolins are scaffolding proteins that are integral components of caveolae, flask-shaped invaginations in the membranes of all mammalian cells. Caveolin-1 and -2 are expressed ubiquitously, whereas caveolin-3 is found only in muscle. The role of caveolin-3 in heart muscle disease is controversial.
METHODS AND RESULTS: The present study was undertaken to assess the effects of left ventricular dysfunction on the expression of caveolin proteins using 2 well characterized models of murine heart failure and failing human heart. Transgenic mice with constitutive overexpression of A(1)-adenosine receptor (A(1)-TG) demonstrated cardiac dilatation and decreased left ventricular function at 10 weeks of age. This was accompanied by a marked decrease in caveolin-3 mRNA and protein levels compared with non-TG control mice. The change in caveolin-3 expression was selective, because levels of caveolin-1 and -2 did not change. Confocal imaging of myocytes isolated from A(1)-TG mice demonstrated a loss of the plate-like appearance of T tubules. Caveolin-3 levels were also reduced in hearts from mice overexpressing tumor necrosis factor α. There was a direct relationship between caveolin-3 expression and fractional shortening in all mice that were studied (r = 0.65; P < .001). Although we could not demonstrate a significant decrease in caveolin-3 levels in failing human heart, we did find a direct correlation (r = 0.7; P < .05) between levels of caveolin-3 protein and Ca(2+)-adenosine triphosphatase, a marker of the heart failure phenotype.
CONCLUSIONS: These results suggest a relationship between left ventricular dysfunction and caveolin-3 levels and suggest that caveolin-3 may provide a novel target for heart failure therapy.
Published In/Presented At
Feiner, E. C., Chung, P., Jasmin, J. F., Zhang, J., Whitaker-Menezes, D., Myers, V., Song, J., Feldman, E. W., Funakoshi, H., Degeorge, B. R., Jr, Yelamarty, R. V., Koch, W. J., Lisanti, M. P., McTiernan, C. F., Cheung, J. Y., Bristow, M. R., Chan, T. O., & Feldman, A. M. (2011). Left ventricular dysfunction in murine models of heart failure and in failing human heart is associated with a selective decrease in the expression of caveolin-3. Journal of cardiac failure, 17(3), 253–263. https://doi.org/10.1016/j.cardfail.2010.10.008
Medicine and Health Sciences
Department of Medicine, Cardiology Division