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

Abstract

BACKGROUND AND PURPOSE:

Pathological cardiac hypertrophy is associated with the expression of a gene profile reminiscent of foetal development. The non selective beta-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 beta-isoform of myosin heavy chain (beta-MHC), and the alpha-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 alpha(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, beta-MHC and skACT mRNA in the left ventricles increased 2.2-fold, 2.0-fold and 12.1-fold, respectively, whereas alpha-MHC and SERCA mRNA levels decreased by approximately 50%. Although propranolol blunted cardiomyocyte growth, with approximately an 11% increase in the LVW/BW ratio, it enhanced the expression of ANP, beta-MHC and skACT genes (10.5-fold, 27.7-fold and 22.7-fold, respectively). Propranolol also enhanced phenylephrine-stimulated ANP and beta-MHC gene expression in cultured cardiomyocytes. Similar results were obtained with metoprolol, a selective beta(1)-adrenoceptor antagonist, but not with ICI 118551, a beta(2)-adrenoceptor antagonist.

CONCLUSIONS AND IMPLICATIONS:

Propranolol enhances expression of the hypertrophy-associated foetal genes mainly via the beta(1)-adrenoceptor blockade. Our results also suggest that, in pressure-overloaded hearts, cardiomyocyte growth and foetal gene expression occur as independent processes.

• Authors: M Patrizio, M Musumeci, T Stati, P Fasanaro, S Palazzesi, L Catalano, G Marano
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 152 Issue 2 Pg. 216-22 (Sep 2007) ISSN: 0007-1188 [Print] England
• PMID: 17592507 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adrenergic beta-Antagonists
• Propranolol

Topics

• Adrenergic beta-Antagonists (pharmacology)
• Animals
• Cardiomegaly (drug therapy)
• Cells, Cultured
• Gene Expression Profiling
• Gene Expression Regulation (drug effects)
• Hypertrophy, Left Ventricular (pathology, prevention & control)
• Male
• Mice
• Mice, Inbred C57BL
• Myocytes, Cardiac (drug effects, metabolism)
• Propranolol (pharmacology)
• Rats
• Rats, Wistar