Cardiac-specific overexpression of caveolin-3 attenuates cardiac hypertrophy and increases natriuretic peptide expression and signaling

Yousuke T. Horikawa, Mathivadhani Panneerselvam, Yoshitaka Kawaraguchi, Yasuo M. Tsutsumi, Sameh S. Ali, Ravi C. Balijepalli, Fiona Murray, Brian P. Head, Ingrid R. Niesman, Timo Rieg, Volker Vallon, Paul A. Insel, Hemal H. Patel, David M. Roth*

*Corresponding author for this work

Research output: Contribution to journalArticle

57 Citations (Scopus)

Abstract

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

Original languageEnglish
Pages (from-to)2273-2283
Number of pages11
JournalJournal of the American College of Cardiology
Volume57
Issue number22
DOIs
Publication statusPublished - 31 May 2011

Keywords

  • hypertrophy
  • cardiomyocyte hypertrophy
  • mice
  • caveolae
  • heart
  • atrial natriuretic peptide (ANP)
  • pathway
  • brain natriuretic peptide (BNP)
  • myocytes
  • protection
  • caveolin
  • receptor
  • transduction
  • remodeling
  • pressure
  • reperfusion

Cite this

Horikawa, Y. T., Panneerselvam, M., Kawaraguchi, Y., Tsutsumi, Y. M., Ali, S. S., Balijepalli, R. C., ... Roth, D. M. (2011). Cardiac-specific overexpression of caveolin-3 attenuates cardiac hypertrophy and increases natriuretic peptide expression and signaling. Journal of the American College of Cardiology, 57(22), 2273-2283. https://doi.org/10.1016/j.jacc.2010.12.032

Cardiac-specific overexpression of caveolin-3 attenuates cardiac hypertrophy and increases natriuretic peptide expression and signaling. / Horikawa, Yousuke T.; Panneerselvam, Mathivadhani; Kawaraguchi, Yoshitaka; Tsutsumi, Yasuo M.; Ali, Sameh S.; Balijepalli, Ravi C.; Murray, Fiona; Head, Brian P.; Niesman, Ingrid R.; Rieg, Timo; Vallon, Volker; Insel, Paul A.; Patel, Hemal H.; Roth, David M.

In: Journal of the American College of Cardiology, Vol. 57, No. 22, 31.05.2011, p. 2273-2283.

Research output: Contribution to journalArticle

Horikawa, YT, Panneerselvam, M, Kawaraguchi, Y, Tsutsumi, YM, Ali, SS, Balijepalli, RC, Murray, F, Head, BP, Niesman, IR, Rieg, T, Vallon, V, Insel, PA, Patel, HH & Roth, DM 2011, 'Cardiac-specific overexpression of caveolin-3 attenuates cardiac hypertrophy and increases natriuretic peptide expression and signaling', Journal of the American College of Cardiology, vol. 57, no. 22, pp. 2273-2283. https://doi.org/10.1016/j.jacc.2010.12.032
Horikawa, Yousuke T. ; Panneerselvam, Mathivadhani ; Kawaraguchi, Yoshitaka ; Tsutsumi, Yasuo M. ; Ali, Sameh S. ; Balijepalli, Ravi C. ; Murray, Fiona ; Head, Brian P. ; Niesman, Ingrid R. ; Rieg, Timo ; Vallon, Volker ; Insel, Paul A. ; Patel, Hemal H. ; Roth, David M. / Cardiac-specific overexpression of caveolin-3 attenuates cardiac hypertrophy and increases natriuretic peptide expression and signaling. In: Journal of the American College of Cardiology. 2011 ; Vol. 57, No. 22. pp. 2273-2283.
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abstract = "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",
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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

VL - 57

SP - 2273

EP - 2283

JO - Journal of the American College of Cardiology

JF - Journal of the American College of Cardiology

SN - 0735-1097

IS - 22

ER -