Published Online
on July 7, 2003

A more recent version of this article appeared on August 1, 2003

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Submitted on November 15, 2002
Revised on December 26, 2002

Adenovirus-Mediated Overexpression of Caveolin-3 Inhibits Rat Cardiomyocyte Hypertrophy

Akimasa Koga; Naoki Oka^*; Toshio Kikuchi; Hiroshi Miyazaki; Seiya Kato; and Tsutomu Imaizumi

From the Department of Internal Medicine III (A.K., N.O., T.K., H.M., T.I.), the Cardiovascular Research Institute (T.I.), and the Department of Pathology (S.K.), Kurume University School of Medicine, Kurume, Japan.

^* To whom correspondence should be addressed. E-mail: noka{at}med.kurume-u.ac.jp.

Abstract--Caveolae are omega-shaped organelles of the cell surface. The protein caveolin-3, a structural component of cardiac caveolae, is associated with cellular signaling. To investigate the effect of adenovirus-mediated overexpression of caveolin-3 on hypertrophic responses in cardiomyocytes, we constructed an adenovirus that encoded human wild-type caveolin-3 (Ad.Cav-3), mutant caveolin-3 (Ad.Cav-3), or bacterial -galactosidase (Ad.LacZ). This mutant has been reported to cause human limb-girdle muscular dystrophy. It lacks 9 nucleotides in the caveolin scaffolding domain and behaves in a dominant-negative fashion. Rat neonatal cardiomyocytes were infected with the virus and then harvested 36 hours after infection. In noninfected cells, phenylephrine (PE) and endothelin-1 (ET) increased cell size and [³H]leucine incorporation, along with the induction of sarcomeric reorganization and the reexpression of -myosin heavy chain, indicating myocyte hypertrophy. Infection with Ad.LacZ had no effect on those parameters. Ad.Cav-3 prevented the PE- and ET-induced increases in cell size, leucine incorporation, sarcomeric reorganization, and reexpression of -myosin heavy chain. Ad.Cav-3 also blocked the PE- and ET-induced phosphorylations of extracellular signal-regulated kinases (ERKs) but did not affect c-Jun amino-terminal kinase and p38 mitogen-activated protein kinase activities. In contrast, Ad.Cav-3 significantly augmented hypertrophic responses to ET, which were associated with increased ET-induced phosphorylation of ERK1/2. These results suggest that caveolin-3 behaves as a negative regulator of hypertrophic responses, probably through suppression of ERK1/2 activity.

Key words: hypertrophy • receptors, adrenergic • endothelin • myocytes • gene expression

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