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Cardiac‐Specific Overexpression of Caveolin‐3 Enhances Akt Phosphorylation
Author(s) -
Horikawa Yousuke T,
Patel Hemal H,
Tsutsumi Yasuo M,
Yokoyama Utako,
Insel Paul A,
Roth David M
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.6.a794-b
Subject(s) - protein kinase b , phosphorylation , caveolin 3 , pi3k/akt/mtor pathway , biology , medicine , transgene , endocrinology , cardiac myocyte , caveolae , genetically modified mouse , sarcolemma , microbiology and biotechnology , signal transduction , chemistry , myocyte , biochemistry , gene
Caveolin‐3 (Cav3), a membrane protein that helps define lipid raft/caveolar domains, is a potent activator of PI3‐K/Akt signaling, an important pathway in cardiac protection. We hypothesized that cardiac‐directed overexpression of Cav3 augments PI3‐K/Akt cardiac protective signaling in vivo. Mouse Cav3 was cloned into a vector containing the α‐myosin heavy chain promoter to allow for cardiac myocyte‐specific expression of Cav3. A transgenic (Tg) mouse line was derived with a 5.5‐fold increase in Cav3 mRNA and a 2.4‐fold increase in Cav3 protein that localized specifically to the sarcolemma. No significant increase in Cav3 expression was observed in lung, liver, brain, or skeletal muscle from Tg‐positive mice. Electron microscopy revealed enhanced formation of caveolae on the sarcolemmal membranes of Tg‐positive mice compared to Tg‐negative littermate controls and no apparent structural defects in the heart. Echocardiography of 7–9 month old Tg‐positive and Tg‐negative mice showed no significant differences in cardiac function. Hearts excised from Tg‐positive mice had a 1.5‐fold increase in basal phosphorylation of Akt (p<0.05, n=6 TG positive, 4 Tg‐negative). Treatment with isoflurane (30 min, 1.4%), an agent that produces cardiac protection and activates Akt signaling, produced a 2.5‐fold greater increase in phosphorylation of Akt in Tg‐positive vs. Tg‐negative animals (n=3/group). These results reveal that cardiac‐specific overexpression of Cav3 produces a phenotype in mice with greater basal and stimulated PI3‐K/Akt signaling, thus suggesting that approaches to increase Cav3 expression may provide a novel means to augment cardiac protection and perhaps other effects mediated by PI3‐K/Akt.