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Isolation and Culture of Adult Mouse Cardiomyocytes for Cell Signaling and in vitro Cardiac Hypertrophy
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Isolation and Culture of Adult Mouse Cardiomyocytes for Cell Signaling and in vitro Cardiac Hypertrophy

Published on: May 21, 2014

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GDF11 Modulates Ca2+-Dependent Smad2/3 Signaling to Prevent Cardiomyocyte Hypertrophy

Javier Duran1, Mayarling Francisca Troncoso2, Daniel Lagos3

  • 1Programa de Fisiología y Biofísica, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago 8389100, Chile. javiadg@ug.uchile.cl.

International Journal of Molecular Sciences
|May 23, 2018
PubMed

Insights

Growth differentiation factor 11 (GDF11) prevents cardiac hypertrophy by increasing intracellular calcium and activating Smad2/3 signaling. This mechanism involves the inositol 1,4,5-trisphosphate pathway, suggesting GDF11 as a therapeutic target.

Area of Science:

  • Cardiovascular Biology
  • Cell Signaling
  • Molecular Medicine

Background:

  • Growth differentiation factor 11 (GDF11), a TGF-β family member, inhibits cardiac hypertrophy.
  • Calcium (Ca2+) signaling regulates cardiomyocyte growth, but its role in GDF11's effects is unclear.

Purpose of the Study:

  • To elucidate the role of Ca2+-dependent mechanisms in GDF11's regulation of cardiac hypertrophy.
  • To investigate the interplay between GDF11, Ca2+ signaling, and the Smad2/3 pathway in cardiomyocytes.

Main Methods:

  • Neonatal rat cardiomyocytes were treated with GDF11 and assessed for intracellular Ca2+ levels using BAPTA-AM and inositol 1,4,5-trisphosphate (IP3) pathway inhibitors.
  • Smad2/3 phosphorylation and activity were measured following GDF11 treatment.
  • Cardiomyocytes were exposed to hypertrophic agents (testosterone or phenylephrine) with or without GDF11 pretreatment.
  • Smad2 and Smad3 were downregulated using siRNA to assess their role in GDF11's antihypertrophic effects.

Main Results:

  • GDF11 induced intracellular Ca2+ increases, mediated by the IP3 pathway.
  • GDF11 enhanced Smad2/3 phosphorylation and activity, which was dependent on IP3-mediated Ca2+ release.
  • GDF11 pretreatment significantly blunted testosterone- or phenylephrine-induced cardiomyocyte hypertrophy (size and [3H]-leucine incorporation).
  • siRNA-mediated downregulation of Smad2/3 abolished the antihypertrophic effects of GDF11.

Conclusions:

  • GDF11 prevents cardiomyocyte hypertrophy by modulating intracellular Ca2+ signaling through the IP3 pathway.
  • The Smad2/3 pathway is essential for mediating GDF11's antihypertrophic effects.
  • GDF11's action on Ca2+ signaling and Smad2/3 activation represents a potential therapeutic strategy for cardiac hypertrophy.
Keywords:
Ca2+ signalingSmad2/3 proteinscardiomyocyte hypertrophygrowth differentiation factor 11

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