TY - JOUR
T1 - Propranolol causes a paradoxical enhancement of cardiomyocyte foetal gene response to hypertrophic stimuli
AU - Patrizio, M.
AU - Musumeci, M.
AU - Stati, T.
AU - Fasanaro, P.
AU - Palazzesi, S.
AU - Catalano, L.
AU - Marano, G.
PY - 2007/9
Y1 - 2007/9
N2 - 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.
AB - 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.
KW - Gene expression
KW - Heart
KW - Hypertrophy
KW - Phenylephrine
KW - Pressure overload
KW - Propranolol
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U2 - 10.1038/sj.bjp.0707350
DO - 10.1038/sj.bjp.0707350
M3 - Article
C2 - 17592507
AN - SCOPUS:34948892558
VL - 152
SP - 216
EP - 222
JO - British Journal of Pharmacology
JF - British Journal of Pharmacology
SN - 0007-1188
IS - 2
ER -