Adenovirus-mediated overexpression of caveolin-3 inhibits rat cardiomyocyte hypertrophy.
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-3Delta), or bacterial beta-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 beta-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 beta-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-3Delta 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.
Koga
Akimasa
A
Department of Internal Medicine III, Kurume University School of Medicine, 67 Asahi-machi, Kurume 830-0011, Japan.
Oka
Naoki
N
Kikuchi
Toshio
T
Miyazaki
Hiroshi
H
Kato
Seiya
S
Imaizumi
Tsutomu
T
D000256:Adenoviridae / Q000235:genetics*; D058646:Adrenergic alpha-1 Receptor Agonists; D000818:Animals; D006332:Cardiomegaly / Q000209:etiology; D051244:Caveolin 3; D022461:Caveolins / Q000235:genetics* / Q000502:physiology*; D048429:Cell Size / Q000187:drug effects; D002478:Cells, Cultured; D019332:Endothelin-1 / Q000494:pharmacology; D015870:Gene Expression; D005822:Genetic Vectors; D006801:Humans; D007930:Leucine / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009154:Mutation; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000378:metabolism / Q000648:ultrastructure; D018995:Myosin Heavy Chains / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D011994:Recombinant Proteins / Q000032:analysis / Q000378:metabolism; D012518:Sarcomeres / Q000648:ultrastructure
D058646:Adrenergic alpha-1 Receptor Agonists; C495549:Cav3 protein, rat; D051244:Caveolin 3; D022461:Caveolins; D019332:Endothelin-1; D011994:Recombinant Proteins; D020928:Mitogen-Activated Protein Kinases; D018995:Myosin Heavy Chains; D007930:Leucine