Propranolol causes a paradoxical enhancement of cardiomyocyte foetal gene response to hypertrophic stimuli

M. Patrizio, M. Musumeci, T. Stati, P. Fasanaro, S. Palazzesi, L. Catalano, G. Marano

Research output: Contribution to journalArticlepeer-review

Abstract

Background and purpose: Pathological cardiac hypertrophy is associated with the expression of a gene profile reminiscent of foetal development. The non selective β-adrenoceptor antagonist propranolol is able to blunt cardiomyocyte hypertrophic response in pressure-overloaded hearts. It remains to be determined whether propranolol also attenuates the expression of hypertrophy-associated foetal genes. Experimental approach: To address this question, the foetal gene programme, of which atrial natriuretic peptide (ANP), the β-isoform of myosin heavy chain (β-MHC), and the α-skeletal muscle isoform of actin (skACT) are classical members, was induced by thoracic aortic coarctation (TAC) in C57BL/6 mice, or by phenylephrine, a selective α 1-adrenoceptor agonist, in cultured rat neonatal cardiomyocytes. Key results: In TAC mice, the left ventricular weight-to-body weight (LVW/BW) ratio increased by 35% after 2 weeks. Levels of ANP, β-MHC and skACT mRNA in the left ventricles increased 2.2-fold, 2.0-fold and 12.1-fold, respectively, whereas α-MHC and SERCA mRNA levels decreased by ≈ 50%. Although propranolol blunted cardiomyocyte growth, with approximately an 11% increase in the LVW/BW ratio, it enhanced the expression of ANP, β-MHC and skACT genes (10.5-fold, 27.7-fold and 22.7-fold, respectively). Propranolol also enhanced phenylephrine-stimulated ANP and β-MHC gene expression in cultured cardiomyocytes. Similar results were obtained with metoprolol, a selective β 1-adrenoceptor antagonist, but not with ICI 118551, a β 2-adrenoceptor antagonist. Conclusions and implications: Propranolol enhances expression of the hypertrophy-associated foetal genes mainly via the β 1-adrenoceptor blockade. Our results also suggest that, in pressure-overloaded hearts, cardiomyocyte growth and foetal gene expression occur as independent processes.

Original languageEnglish
Pages (from-to)216-222
Number of pages7
JournalBritish Journal of Pharmacology
Volume152
Issue number2
DOIs
Publication statusPublished - Sep 2007

Keywords

  • Gene expression
  • Heart
  • Hypertrophy
  • Phenylephrine
  • Pressure overload
  • Propranolol

ASJC Scopus subject areas

  • Pharmacology

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