Caveolin-3 Knock-out Mice Develop a Progressive Cardiomyopathy and Show Hyperactivation of the p42/44 MAPK Cascade

Abstract

A growing body of evidence suggests that muscle cell caveolae may function as specialized membrane microdomains in which the dystrophin-glycoprotein complex and cellular signaling molecules reside. Caveolin-3 (Cav-3) is the only caveolin family member expressed in striated muscle cell types (cardiac and skeletal). Interestingly, skeletal muscle fibers from Cav-3 (؊/؊) knockout mice show a number of myopathic changes, consistent with a mild-to-moderate muscular dystrophy phenotype. However, it remains unknown whether a loss of Cav-3 affects the phenotypic behavior cardiac myocytes in vivo. Here, we present a detailed characterization of the hearts of Cav-3 knock-out mice. We show that these mice develop a progressive cardiomyopathic phenotype. At four months of age, Cav-3 knock-out hearts display significant hypertrophy, dilation, and reduced fractional shortening, as revealed by gated cardiac MRI and transthoracic echocardiography. Histological analysis reveals marked cardiac myocyte hypertrophy, with accompanying cellular infiltrates and progressive interstitial/peri-vascular fibrosis. Interestingly, loss of Cav-3 expression in the heart does not change the expression or the membrane association of the dystrophin-glycoprotein (DG) complex. However, a marker of the DG complex, ␣-sarcoglycan, was specifically excluded from lipid raft domains in the absence of Cav-3. Because activation of the Ras-p42/44 MAPK pathway in cardiac myocytes can drive cardiac hypertrophy, we next assessed the activation state of this pathway using a phospho-specific antibody probe. We show that p42/44 MAPK (ERK1/2) is hyperactivated in hearts derived from Cav-3 knock-out mice. These results are consistent with previous in vitro data demonstrating that caveolins may function as negative regulators of the p42/44 MAPK cascade. Taken together, our data argue that loss of Cav-3 expression is sufficient to induce a molecular program leading to cardiac myocyte hypertrophy and cardiomyopathy.

Inducible Fgf13 ablation enhances caveolae-mediated cardioprotection during cardiac pressure overload

“…The signaling pathways associated with caveolae, which compartmentalize receptors, ion channels, and signaling effectors (56,57), have generally been characterized as cardioprotective. The link between caveolae and cardiac hypertrophy was first established in Cav3 KO mice, which display significant hypertrophy, dilation, and reduced fractional shortening associated with hyperactivation of the maladaptive p42/44 MAPK pathway (44). In contrast, adenoviral-mediated overexpression of Cav3 in isolated cardiomyocytes conferred protection from phenylephrineinduced hypertrophy (58), and transgenic mice with cardiomyocytespecific overexpression of Cav3 demonstrated attenuation of cardiac hypertrophy and preservation of function following TAC (15).…”

“…To date, two families of structural proteins-caveolins and cavins-have been shown to regulate caveolae biogenesis and morphology (16). Disruption of cavin-caveolin complexes can alter caveolae abundance and contribute to multisystemic disease, including cardiac arrhythmias and hypertrophy, lipodystrophy, and muscular dystrophy (44)(45)(46)(47). However, the precise mechanisms by which cavins assemble with caveolins, especially in cardiac muscle, remain unclear.…”

Myocardial hypertrophy in the absence of external stimuli is induced by angiogenesis in mice

“…Accordingly, increase in caveolin-1 expression has been associated with hypertension and its absence with vasodilatation due to eNOS hyperactivation (15,16). Moreover, the loss of caveolin-3 expression activates p42/44 MAPK cascade and induces cardiac hypertrophy (17). Recently it was suggested that NO controls the levels of RGS (10).…”

Caveolin Interacts with the Angiotensin II Type 1 Receptor during Exocytic Transport but Not at the Plasma Membrane

“…In the present study we have now shown that Cav1 and Cav3 also act as trafficking chaperones for a seven transmembrane-spanning GPCR. In this context, it is worth noting that Cav1 and Cav3 knockout mice suffer from a variety of cardiovascular pathologies (38,55,56). Given that the AT 1 -R has a major role in maintaining cardiovascular homeostasis, it is tempting to speculate that alterations in AT 1 -R levels, and perhaps those of other GPCRs (see below), may contribute to some of the cardiovascular changes observed in mice lacking caveolin.…”