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Induction of Endothelial Differentiation in Cardiac Progenitor Cells Under Low Serum Conditions
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Distinct signaling functions for Shc isoforms in the heart

Maria Obreztchikova1, Hasnae Elouardighi, Mengfei Ho

  • 1Department of Pharmacology, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA.

The Journal of Biological Chemistry
|May 16, 2006
PubMed

Insights

This study reveals how thrombin signaling impacts cardiac fibroblasts and cardiomyocytes, highlighting the role of Shc proteins in ventricular remodeling and heart failure development. It identifies p66Shc as a potential mediator of cardiomyocyte apoptosis.

Area of Science:

  • Cardiovascular Biology
  • Cell Signaling
  • Molecular Medicine

Background:

  • Thrombin activates protease-activated receptor-1 (PAR-1), influencing cardiomyocyte growth and cardiac fibroblast extracellular matrix remodeling.
  • Ventricular remodeling is a key process in the transition to heart failure.

Purpose of the Study:

  • To investigate the role of Shc proteins in PAR-1-dependent signaling pathways.
  • To understand the mechanisms underlying thrombin-induced ventricular remodeling.

Main Methods:

  • Examined Shc protein phosphorylation in cardiac fibroblasts and cardiomyocytes.
  • Utilized pertussis toxin and specific agonists to probe signaling pathways.
  • Assessed p66Shc protein expression in neonatal and adult cardiomyocytes.

Main Results:

  • Thrombin induced Shc phosphorylation via epidermal growth factor receptor (EGFR) transactivation in cardiac fibroblasts, involving MEK for p66Shc-Ser(36) phosphorylation.
  • Beta(2)-adrenergic receptors activated ERK via a distinct EGFR transactivation pathway in fibroblasts, independent of Shc.
  • Thrombin triggered MEK-dependent p66Shc-Ser(36) phosphorylation in cardiomyocytes, but not via EGFR transactivation.
  • p66Shc expression was present in neonatal but induced in adult cardiomyocytes by a Galpha(q) agonist, requiring protein kinase C and MEK activity.

Conclusions:

  • Identified novel regulation of Shc isoforms in receptor-dependent pathways contributing to cardiac hypertrophy and heart failure.
  • p66Shc is a potential mediator of cardiomyocyte apoptosis and heart failure, induced by Galpha(q) agonists and activated by PAR-1 signaling.

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