Calcineurin-mediated hypertrophy protects cardiomyocytes from apoptosis in vitro and in vivo. An apoptosis-independent model of dilated heart failure

Leon J. De Windt, Hae W. Lim, Tyler Taigen, Detlef Wencker, Gianluigi Condorelli, Gerald W. Dorn, Richard N. Kitsis, Jeffery D. Molkentin

Research output: Contribution to journalArticle

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Abstract

We have previously shown that the calcium-calmodulin-regulated phosphatase calcineurin (PP2B) is sufficient to induce cardiac hypertrophy that transitions to heart failure in transgenic mice. Given the rapid onset of heart failure in these mice, we hypothesized that calcineurin signaling would stimulate myocardial cell apoptosis. However, utilizing multiple approaches, we determined that calcineurin-mediated hypertrophy protected cardiac myocytes from apoptosis, suggesting a model of heart failure that is independent of apoptosis. Adenovirally mediated gene transfer of a constitutively active calcineurin cDNA (AdCnA) was performed in cultured neonatal rat cardiomyocytes to elucidate the mechanism whereby calcineurin affected myocardial cell viability. AdCnA infection, which induced myocyte hypertrophy and atrial natriuretic factor expression, protected against apoptosis induced by 2-deoxyglucose or staurosporine, as assessed by terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL) labeling, caspase-3 activation, DNA laddering, and cellular morphology. The level of protection conferred by AdCnA was similar to that of adenoviral Bcl-X(L) gene transfer or hypertrophy induced by phenylephrine. In vivo, failing hearts from calcineurin-transgenic mice did not demonstrate increased TUNEL labeling and, in fact, demonstrated a resistance to ischemia/reperfusion-induced apoptosis. We determined that the mechanism whereby calcineurin afforded protection from apoptosis was partially mediated by nuclear factor of activated T cells (NFAT3) signaling and partially by Akt/protein kinase B (PKB) signaling. Although calcineurin activation protected myocytes from apoptosis, inhibition of calcineurin with cyclosporine was not sufficient to induce TUNEL labeling in Gqα-transgenic mice or in cultured cardiomyocytes. Collectively, these data identify a calcineurin-dependent mouse model of dilated heart failure that is independent of apoptosis.

Original languageEnglish (US)
Pages (from-to)255-263
Number of pages9
JournalCirculation Research
Volume86
Issue number3
StatePublished - Feb 18 2000

Fingerprint

Calcineurin
Cardiac Myocytes
Hypertrophy
Heart Failure
Apoptosis
In Situ Nick-End Labeling
Transgenic Mice
Muscle Cells
NFATC Transcription Factors
In Vitro Techniques
Proto-Oncogene Proteins c-akt
Staurosporine
DNA Nucleotidylexotransferase
Deoxyglucose
Cardiomegaly
Atrial Natriuretic Factor
Phenylephrine
Calmodulin
Caspase 3
Cyclosporine

Keywords

  • Apoptosis
  • Calcineurin
  • Cardiac hypertrophy
  • Caspase-3
  • Phenylephrine

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

De Windt, L. J., Lim, H. W., Taigen, T., Wencker, D., Condorelli, G., Dorn, G. W., ... Molkentin, J. D. (2000). Calcineurin-mediated hypertrophy protects cardiomyocytes from apoptosis in vitro and in vivo. An apoptosis-independent model of dilated heart failure. Circulation Research, 86(3), 255-263.

Calcineurin-mediated hypertrophy protects cardiomyocytes from apoptosis in vitro and in vivo. An apoptosis-independent model of dilated heart failure. / De Windt, Leon J.; Lim, Hae W.; Taigen, Tyler; Wencker, Detlef; Condorelli, Gianluigi; Dorn, Gerald W.; Kitsis, Richard N.; Molkentin, Jeffery D.

In: Circulation Research, Vol. 86, No. 3, 18.02.2000, p. 255-263.

Research output: Contribution to journalArticle

De Windt, LJ, Lim, HW, Taigen, T, Wencker, D, Condorelli, G, Dorn, GW, Kitsis, RN & Molkentin, JD 2000, 'Calcineurin-mediated hypertrophy protects cardiomyocytes from apoptosis in vitro and in vivo. An apoptosis-independent model of dilated heart failure', Circulation Research, vol. 86, no. 3, pp. 255-263.
De Windt, Leon J. ; Lim, Hae W. ; Taigen, Tyler ; Wencker, Detlef ; Condorelli, Gianluigi ; Dorn, Gerald W. ; Kitsis, Richard N. ; Molkentin, Jeffery D. / Calcineurin-mediated hypertrophy protects cardiomyocytes from apoptosis in vitro and in vivo. An apoptosis-independent model of dilated heart failure. In: Circulation Research. 2000 ; Vol. 86, No. 3. pp. 255-263.
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