GDF15/MIC-1 functions as a protective and antihypertrophic factor released from the myocardium in association with SMAD protein activation

Jian Xu, Thomas R. Kimball, John N. Lorenz, David A. Brown, Asne R. Bauskin, Raisa Klevitsky, Timothy Hewett, Samuel N. Breit, Jeffery D. Molkentin

Research output: Contribution to journalArticle

272 Citations (Scopus)

Abstract

Here we identified growth-differentiation factor 15 (GDF15) (also known as MIC-1), a secreted member of the transforming growth factor (TGF)-β superfamily, as a novel antihypertrophic regulatory factor in the heart. GDF15 is not expressed in the normal adult heart but is induced in response to conditions that promote hypertrophy and dilated cardiomyopathy. To elucidate the function of GDF15 in the heart, we generated transgenic mice with cardiac-specific overexpression. GDF15 transgenic mice were normal but were partially resistant to pressure overload-induced hypertrophy. Expression of GDF15 in neonatal cardiomyocyte cultures by adenoviral-mediated gene transfer antagonized agonist-induced hypertrophy in vitro. Transient expression of GDF15 outside the heart by intravenous adenoviral delivery, or by direct injection of recombinant GDF15 protein, attenuated ventricular dilation and heart failure in muscle lim protein gene-targeted mice through an endocrine effect. Conversely, examination of Gdf15 gene-targeted mice showed enhanced cardiac hypertrophic growth following pressure overload stimulation. Gdf15 gene-targeted mice also demonstrated a pronounced loss in ventricular performance following only 2 weeks of pressure overload stimulation, whereas wild-type controls maintained function. Mechanistically, GDF15 stimulation promoted activation of SMAD2/3 in cultured neonatal cardiomyocytes. Overexpression of SMAD2 attenuated cardiomyocyte hypertrophy similar to GDF15 treatment, whereas overexpression of the inhibitory SMAD proteins, SMAD6/7, reversed the antihypertrophic effects of GDF15. These results identify GDF15 as a novel autocrine/endocrine factor that antagonizes the hypertrophic response and loss of ventricular performance, possibly through a mechanism involving SMAD proteins.

Original languageEnglish (US)
Pages (from-to)342-350
Number of pages9
JournalCirculation Research
Volume98
Issue number3
DOIs
StatePublished - Feb 2006
Externally publishedYes

Fingerprint

Growth Differentiation Factor 15
Myocardium
Proteins
Hypertrophy
Cardiac Myocytes
Pressure
Transgenic Mice
Genes
Protective Factors
Muscle Proteins
Dilated Cardiomyopathy
Transforming Growth Factors

Keywords

  • Cardiac
  • Growth factors
  • Hypertrophy
  • Mouse genetics
  • Signaling

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

GDF15/MIC-1 functions as a protective and antihypertrophic factor released from the myocardium in association with SMAD protein activation. / Xu, Jian; Kimball, Thomas R.; Lorenz, John N.; Brown, David A.; Bauskin, Asne R.; Klevitsky, Raisa; Hewett, Timothy; Breit, Samuel N.; Molkentin, Jeffery D.

In: Circulation Research, Vol. 98, No. 3, 02.2006, p. 342-350.

Research output: Contribution to journalArticle

Xu, Jian ; Kimball, Thomas R. ; Lorenz, John N. ; Brown, David A. ; Bauskin, Asne R. ; Klevitsky, Raisa ; Hewett, Timothy ; Breit, Samuel N. ; Molkentin, Jeffery D. / GDF15/MIC-1 functions as a protective and antihypertrophic factor released from the myocardium in association with SMAD protein activation. In: Circulation Research. 2006 ; Vol. 98, No. 3. pp. 342-350.
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AU - Brown, David A.

AU - Bauskin, Asne R.

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AB - Here we identified growth-differentiation factor 15 (GDF15) (also known as MIC-1), a secreted member of the transforming growth factor (TGF)-β superfamily, as a novel antihypertrophic regulatory factor in the heart. GDF15 is not expressed in the normal adult heart but is induced in response to conditions that promote hypertrophy and dilated cardiomyopathy. To elucidate the function of GDF15 in the heart, we generated transgenic mice with cardiac-specific overexpression. GDF15 transgenic mice were normal but were partially resistant to pressure overload-induced hypertrophy. Expression of GDF15 in neonatal cardiomyocyte cultures by adenoviral-mediated gene transfer antagonized agonist-induced hypertrophy in vitro. Transient expression of GDF15 outside the heart by intravenous adenoviral delivery, or by direct injection of recombinant GDF15 protein, attenuated ventricular dilation and heart failure in muscle lim protein gene-targeted mice through an endocrine effect. Conversely, examination of Gdf15 gene-targeted mice showed enhanced cardiac hypertrophic growth following pressure overload stimulation. Gdf15 gene-targeted mice also demonstrated a pronounced loss in ventricular performance following only 2 weeks of pressure overload stimulation, whereas wild-type controls maintained function. Mechanistically, GDF15 stimulation promoted activation of SMAD2/3 in cultured neonatal cardiomyocytes. Overexpression of SMAD2 attenuated cardiomyocyte hypertrophy similar to GDF15 treatment, whereas overexpression of the inhibitory SMAD proteins, SMAD6/7, reversed the antihypertrophic effects of GDF15. These results identify GDF15 as a novel autocrine/endocrine factor that antagonizes the hypertrophic response and loss of ventricular performance, possibly through a mechanism involving SMAD proteins.

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