Caveolin-1 Null (−/−) Mice Show Dramatic Reductions in Life Span

Abstract

Caveolae are 50-100 nm flask-shaped invaginations of the plasma membrane found in most cell types. Caveolin-1 is the principal protein component of caveolae membranes in nonmuscle cells. The recent development of Cav-1-deficient mice has allowed investigators to study the in vivo functional role of caveolae in the context of a whole animal model, as these mice lack morphologically detectable caveolae membrane domains. Surprisingly, Cav-1 null mice are both viable and fertile. However, it remains unknown whether loss of caveolin-1 significantly affects the overall life span of these animals. To quantitatively determine whether loss of Cav-1 gene expression confers any survival disadvantages with increasing age, we generated a large cohort of mice (n = 180), consisting of Cav-1 wild-type (+/+) (n = 53), Cav-1 heterozygous (+/-) (n = 70), and Cav-1 knockout (-/-) (n = 57) animals, and monitored their long-term survival over a 2 year period. Here, we show that Cav-1 null (-/-) mice exhibit an approximately 50% reduction in life span, with major declines in viability occurring between 27 and 65 weeks of age. However, Cav-1 heterozygous (+/-) mice did not show any changes in long-term survival, indicating that loss of both Cav-1 alleles is required to mediate a reduction in life span. Mechanistically, these dramatic reductions in life span appear to be secondary to a combination of pulmonary fibrosis, pulmonary hypertension, and cardiac hypertrophy in Cav-1 null mice. Taken together, our results provide the first demonstration that loss of Cav-1 gene expression and caveolae organelles dramatically affects the long-term survival of an organism. In addition, aged Cav-1 null mice may provide a new animal model to study the pathogenesis and treatment of progressive hypertrophic cardiomyopathy and sudden cardiac death syndrome.

The Caveolin-1 Connection to Cell Death and Survival

“…Since this site is phosphorylated in response to a variety of growth factors (insulin, PDGF, EGF) and stress stimuli, including UV irradiation, mechanical and oxidative stress, as well as hyperosmolarity, phosphorylation of Caveolin-1 on Tyr-14 may constitute an important element in cellular stress responses [68][69]. Indeed, although Caveolin-1 knock-out animals are viable and fertile, their ability to respond to specific stress situations, as well as life-span in general is diminished [4][5][17][18]. Phosphorylation of Caveolin-1 on Tyr-14 is also linked to augmented anchorageindependent growth and cell migration via a Grb7-dependent mechanism [57], as well as association with type-I matrix metalloproteinase [70].…”

“…Often, but not always, non-receptor tyrosine kinases of the Src family are involved and phosphorylation is triggered as part of a so-called stress response [11]. The importance of Caveolin-1 in this context is underscored by the fact that Caveolin-1 knock-out mice display a remarkably reduced ability to regenerate specific tissues like the liver and also a dramatic decrease in life span [17][18]. Rather intriguingly, phosphorylation of Caveolin-1 is also considered highly relevant to cell migration and metastasis (see discussion later on).…”

Transcription of the Caveolin-1 Gene Is Differentially Regulated in Lung Type I Epithelial and Endothelial Cell Lines

“…In intact animals loss of caveolin-1 leads to lung abnormalities at 2-4 months, about the same postnatal time point that caveolin-1␣ is first detectable by immunohistochemistry in type I cells in normal animals (4). The pulmonary phenotype appears to contribute to the shortened life span of the null animals although there are uncertainties about the actual cause of early death (8).…”

Cytoplasmic provenance of STAT3 and PY-STAT3 in the endolysosomal compartments in pulmonary arterial endothelial and smooth muscle cells: implications in pulmonary arterial hypertension

“…That the increase in PY-STAT3 levels was seen before the onset of PAH in MCT-treated rats (19,24) and that the introduction of a cav-1 scaffolding domain peptide blocked PY-STAT3 hyperactivation and ameliorated MCT-induced PAH (19) indicated that STAT3 played a role in the initiation of PAH, at least in this animal model. Moreover, Park and colleagues (33) reported the hyperactivation of PY-STAT3 in lungs of cav-1 Ϫ/Ϫ mice, which spontaneously developed PAH. Additionally, the increase in PY-STAT3 levels has now been confirmed in pulmonary arterial lesions of idiopathic PAH in humans (23), and a similar increase in STAT3 was also reported in lungs of mice with hypoxiainduced PAH (53).…”