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Phosphorylation of Akt/GSK-3β/eNOS amplifies 5-HT2B receptor blockade mediated anti-hypertrophic effect in rats

Saurabh Bharti1, Ratnakar Singh, S S Chauhan

  • 1Department of Pharmacology, All India Institute of Medical Sciences, New Delhi 110 029, India.

FEBS Letters
|January 3, 2012
PubMed

Insights

SB-204741, a 5-HT(2B) receptor blocker, reduced cardiac hypertrophy by improving heart function and structure. Co-treatment with a GSK-3β inhibitor enhanced these protective effects, highlighting a key molecular pathway.

Area of Science:

  • Cardiovascular Pharmacology
  • Molecular Cardiology
  • Drug Discovery

Background:

  • Cardiac hypertrophy is a maladaptive response to stress, leading to myocardial dysfunction.
  • The 5-HT(2B) receptor and GSK-3β signaling pathways are implicated in cardiac remodeling.
  • Understanding the interplay between these pathways is crucial for developing novel therapeutics.

Purpose of the Study:

  • To investigate the therapeutic potential of 5-HT(2B) receptor blockade in isoproterenol-induced cardiac hypertrophy.
  • To explore the crosstalk between 5-HT(2B) receptor and GSK-3β signaling in cardiac hypertrophy.
  • To elucidate the molecular mechanisms underlying the anti-hypertrophic effects.

Main Methods:

  • Isoproterenol was used to induce cardiac hypertrophy in a rat model over 28 days.
  • Animals were treated with SB-204741 (5-HT(2B) receptor blocker) and/or SB-216763 (GSK-3β inhibitor).
  • Cardiac function, morphology, and molecular markers of hypertrophy, inflammation, and apoptosis were assessed.

Main Results:

  • SB-204741 treatment significantly improved myocardial function, reduced myocyte size, fibrosis, and architectural damage.
  • SB-204741 suppressed hypertrophic, inflammatory, and apoptotic markers, alongside modulating Akt/GSK-3β/β-catenin/eNOS phosphorylation.
  • Co-treatment with a GSK-3β inhibitor potentiated the anti-hypertrophic effects of SB-204741, indicating pathway synergy.

Conclusions:

  • 5-HT(2B) receptor blockade effectively ameliorates cardiac hypertrophy and its associated pathologies.
  • The anti-hypertrophic effects are mediated, at least in part, by the Akt/GSK-3β/β-catenin/eNOS pathway.
  • Targeting 5-HT(2B) receptors, potentially in combination with GSK-3β inhibitors, offers a promising therapeutic strategy for cardiac hypertrophy.

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