Caveolin-1/3 Double-Knockout Mice Are Viable, but Lack Both Muscle and Non-Muscle Caveolae, and Develop a Severe Cardiomyopathic Phenotype

Abstract

The caveolin gene family consists of caveolins 1, 2, and 3. Caveolins 1 and 2 are co-expressed in many cell types, such as endothelial cells, fibroblasts, smooth muscle cells and adipocytes, where they form a heteroligomeric complex. In contrast, the expression of caveolin-3 is muscle-specific. Thus, the expression of caveolin-1 is required for caveolae formation in nonmuscle cells, while the expression of caveolin-3 drives caveolae formation in striated muscle cell types (cardiac and skeletal). To create a truly caveolae-deficient mouse, we interbred Cav-1 null mice and Cav-3 null mice to generate Cav-1/Cav-3 double-knockout (Cav-1/3 dKO) mice. Here, we report that Cav-1/3 dKO mice are viable and fertile, despite the fact that they lack morphologically identifiable caveolae in endothelia, adipocytes, smooth muscle cells, skeletal muscle fibers, and cardiac myocytes. We also show that these mice are deficient in all three caveolin gene products, as caveolin-2 is unstable in the absence of caveolin-1. Interestingly, Cav-1/3 dKO mice develop a severe cardiomyopathy. Caveolae are 50-to 100-nm omega-shaped invaginations of the plasma membrane found in various tissue types. The principal structural proteins of caveolar membranes are encoded by the caveolin gene family (caveolin-1, -2, and -3). Caveolin-1 and -2 are co-expressed in numerous tissue types, with particularly high expression in adipocytes, endothelial cells, fibroblasts, and epithelial cells.1,2 Caveolin-3, on the other hand, is muscle-specific, being highly expressed in all muscle tissues, such as skeletal muscle, diaphragm, and heart. 3,4 Caveolin-1 and -3 form ϳ350-kd homo-oligomers made up of ϳ14 -16 caveolin monomers. These homooligomers serve as the basic structural units that drive the formation of caveolae membranes. In contrast, Cav-2 either homodimerizes or forms high molecular mass hetero-oligomers with Cav-1.5-7 Cav-1 and Cav-3 are both independently necessary and sufficient to drive caveolae formation in heterologous expression systems, while Cav-2 requires the presence of Cav-1 for proper membrane targeting and stabilization. In the absence of

Cyclin and Caveolin Expression in an Acute Model of Murine Chagasic Myocarditis

“…Previously we reported that caveolin (Cav)-1 and Cav-3 null mice have a cardiomyopathic phenotype. 11,12 Interestingly, in the current paper, we report that acute chagasic myocarditis was accompanied by a reduction in the expression of Cav-1, -2 and -3 in the myocardium. Moreover, there was an increase in the expression of ET-1 and its associated receptors, ET A and ET B , in the myocardium of infected mice.…”

α1-Adrenoreceptors regulate only the caveolae-located subpopulation of cardiac KV4 channels

“…Although there are not electrophysiological studies on Caveolin-3 KO animals, these mice have a number of cardiac alterations including severe hypertrophy and hyperactivation of the MAPK pathway. 30,31 In this regard, cardiac I to becomes Figure 5. aKap100 localizes I to channels and pKa to caveolae.…”

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.…”