TY - JOUR
T1 - Cardiac-specific overexpression of caveolin-3 attenuates cardiac hypertrophy and increases natriuretic peptide expression and signaling
AU - Horikawa, Yousuke T.
AU - Panneerselvam, Mathivadhani
AU - Kawaraguchi, Yoshitaka
AU - Tsutsumi, Yasuo M.
AU - Ali, Sameh S.
AU - Balijepalli, Ravi C.
AU - Murray, Fiona
AU - Head, Brian P.
AU - Niesman, Ingrid R.
AU - Rieg, Timo
AU - Vallon, Volker
AU - Insel, Paul A.
AU - Patel, Hemal H.
AU - Roth, David M.
PY - 2011/5/31
Y1 - 2011/5/31
N2 - Objectives We hypothesized that cardiac myocyte-specific overexpression of caveolin-3 (Cav-3), a muscle-specific caveolin, would alter natriuretic peptide signaling and attenuate cardiac hypertrophy.Background Natriuretic peptides modulate cardiac hypertrophy and are potential therapeutic options for patients with heart failure. Caveolae, microdomains in the plasma membrane that contain caveolin proteins and natriuretic peptide receptors, have been implicated in cardiac hypertrophy and natriuretic peptide localization.Methods We generated transgenic mice with cardiac myocyte-specific overexpression of caveolin-3 (Cav-3 OE) and also used an adenoviral construct to increase Cav-3 in cardiac myocytes.Results The Cav-3 OE mice subjected to transverse aortic constriction had increased survival, reduced cardiac hypertrophy, and maintenance of cardiac function compared with control mice. In left ventricle at baseline, messenger ribonucleic acid for atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) were increased 7- and 3-fold, respectively, in Cav-3 OE mice compared with control subjects and were accompanied by increased protein expression for ANP and BNP. In addition, ventricles from Cav-3 OE mice had greater cyclic guanosine monophosphate levels, less nuclear factor of activated T-cell nuclear translocation, and more nuclear Akt phosphorylation than ventricles from control subjects. Cardiac myocytes incubated with Cav-3 adenovirus showed increased expression of Cav-3, ANP, and Akt phosphorylation. Incubation with methyl-beta-cyclodextrin, which disrupts caveolae, or with wortmannin, a PI3K inhibitor, blocked the increase in ANP expression.Conclusions These results imply that cardiac myocyte-specific Cav-3 OE is a novel strategy to enhance natriuretic peptide expression, attenuate hypertrophy, and possibly exploit the therapeutic benefits of natriuretic peptides in cardiac hypertrophy and heart failure. (J Am Coll Cardiol 2011;57:2273-83) (C) 2011 by the American College of Cardiology Foundation
AB - Objectives We hypothesized that cardiac myocyte-specific overexpression of caveolin-3 (Cav-3), a muscle-specific caveolin, would alter natriuretic peptide signaling and attenuate cardiac hypertrophy.Background Natriuretic peptides modulate cardiac hypertrophy and are potential therapeutic options for patients with heart failure. Caveolae, microdomains in the plasma membrane that contain caveolin proteins and natriuretic peptide receptors, have been implicated in cardiac hypertrophy and natriuretic peptide localization.Methods We generated transgenic mice with cardiac myocyte-specific overexpression of caveolin-3 (Cav-3 OE) and also used an adenoviral construct to increase Cav-3 in cardiac myocytes.Results The Cav-3 OE mice subjected to transverse aortic constriction had increased survival, reduced cardiac hypertrophy, and maintenance of cardiac function compared with control mice. In left ventricle at baseline, messenger ribonucleic acid for atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) were increased 7- and 3-fold, respectively, in Cav-3 OE mice compared with control subjects and were accompanied by increased protein expression for ANP and BNP. In addition, ventricles from Cav-3 OE mice had greater cyclic guanosine monophosphate levels, less nuclear factor of activated T-cell nuclear translocation, and more nuclear Akt phosphorylation than ventricles from control subjects. Cardiac myocytes incubated with Cav-3 adenovirus showed increased expression of Cav-3, ANP, and Akt phosphorylation. Incubation with methyl-beta-cyclodextrin, which disrupts caveolae, or with wortmannin, a PI3K inhibitor, blocked the increase in ANP expression.Conclusions These results imply that cardiac myocyte-specific Cav-3 OE is a novel strategy to enhance natriuretic peptide expression, attenuate hypertrophy, and possibly exploit the therapeutic benefits of natriuretic peptides in cardiac hypertrophy and heart failure. (J Am Coll Cardiol 2011;57:2273-83) (C) 2011 by the American College of Cardiology Foundation
KW - hypertrophy
KW - cardiomyocyte hypertrophy
KW - mice
KW - caveolae
KW - heart
KW - atrial natriuretic peptide (ANP)
KW - pathway
KW - brain natriuretic peptide (BNP)
KW - myocytes
KW - protection
KW - caveolin
KW - receptor
KW - transduction
KW - remodeling
KW - pressure
KW - reperfusion
U2 - 10.1016/j.jacc.2010.12.032
DO - 10.1016/j.jacc.2010.12.032
M3 - Article
SN - 0735-1097
VL - 57
SP - 2273
EP - 2283
JO - Journal of the American College of Cardiology
JF - Journal of the American College of Cardiology
IS - 22
ER -