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Angiotensin II-induced inositol phosphate generation is mediated through tyrosine kinase pathways in cardiomyocytes

V Goutsouliak1, S W Rabkin

  • 1Department of Medicine, University of British Columbia, Vancouver, Canada.

Cellular Signalling
|January 7, 1998
PubMed

Insights

Angiotensin II (ang II) stimulates inositol phosphate production in heart cells via a pathway involving tyrosine phosphorylation (tyr phos). This discovery highlights a novel interaction between G-protein coupled receptors and tyrosine kinases in cardiac function.

Area of Science:

  • Cardiovascular Biology
  • Cell Signaling
  • Molecular Cardiology

Background:

  • G-protein-coupled receptors (GPCRs) mediate diverse cellular responses.
  • Angiotensin II (ang II) is a key regulator of cardiovascular function.
  • Inositol phosphate production is a critical signaling pathway in cardiomyocytes.

Purpose of the Study:

  • To investigate if angiotensin II-mediated inositol phosphate production in the heart involves a tyrosine phosphorylation (tyr phos) dependent pathway.
  • To elucidate the role of tyrosine kinases in ang II signaling in cardiomyocytes.

Main Methods:

  • Primary cardiomyocyte cultures from embryonic chick hearts.
  • Measurement of inositol phosphate accumulation using myo-[3H] inositol and LiCl treatment.
  • Assessment of tyrosine phosphorylation via immunoprecipitation with anti-P-Tyr antibodies.
  • Pharmacological inhibition of tyrosine kinases using genistein and diazdien.
  • Receptor subtype specificity determined using AT1 antagonist losartan and AT2 antagonist PD123319.

Main Results:

  • Angiotensin II significantly increased inositol phosphates (InsP1, InsP2, InsP3) in cardiomyocytes within 1 minute.
  • Tyrosine kinase inhibition with genistein significantly reduced ang II-induced inositol phosphate production.
  • Angiotensin II induced tyrosine phosphorylation of 70 and 195 kDa cardiac proteins, which correlated with peak inositol phosphate production.
  • This tyrosine phosphorylation was primarily mediated by the AT1 receptor, with some involvement of the AT2 receptor.

Conclusions:

  • A novel tyrosine phosphorylation (tyr phos) dependent pathway mediates angiotensin II-induced inositol phosphate production in the heart.
  • This finding demonstrates a significant interaction between G-protein coupled receptors and tyrosine kinases in cardiac signaling.
  • The study provides new insights into the molecular mechanisms regulating cardiac function by angiotensin II.

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