Premium
Propranolol causes a paradoxical enhancement of cardiomyocyte foetal gene response to hypertrophic stimuli
Author(s) -
Patrizio M,
Musumeci M,
Stati T,
Fasanaro P,
Palazzesi S,
Catalano L,
Marano G
Publication year - 2007
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0707350
Subject(s) - medicine , propranolol , endocrinology , phenylephrine , atrial natriuretic peptide , myh6 , muscle hypertrophy , myosin , myocyte , antagonist , biology , myh7 , myosin light chain kinase , receptor , blood pressure , microbiology and biotechnology
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. British Journal of Pharmacology (2007) 152 , 216–222; doi: 10.1038/sj.bjp.0707350