Basic Science and Experimental Study 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 invaginationsinthemembranesofallmammaliancells.Caveolin-1and-2areexpressedubiquitously,whereas caveolin-3 is found only in muscle. The role of caveolin-3 in heart muscle disease is controversial. Methods and Results: Thepresentstudywasundertakentoassesstheeffectsofleftventriculardysfunction 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 A1-adenosine receptor (A1-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 imagingofmyocytesisolatedfromA1-TGmicedemonstratedalossoftheplate-likeappearanceofTtubules. Caveolin-3 levels were also reduced in hearts from mice overexpressing tumor necrosis factor a. There was a direct relationship between caveolin-3 expression and fractional shortening in all mice that were studied (r50.65;P!.001).Althoughwecouldnotdemonstrateasignificantdecreaseincaveolin-3levelsinfailing human heart, we did find a direct correlation (r 5 0.7; P ! .05) between levels of caveolin-3 protein and Ca 2þ -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. (J Cardiac Fail 2011;17:253e263)