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


METHODS
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.


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
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.
Patrizio
M
M
Department of Drug Research and Evaluation, Istituto Superiore di Sanità, Rome, Italy.
Musumeci
M
M
Stati
T
T
Fasanaro
P
P
Palazzesi
S
S
Catalano
L
L
Marano
G
G
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D006332:Cardiomegaly / Q000188:drug therapy; D002478:Cells, Cultured; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects*; D017379:Hypertrophy, Left Ventricular / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D011433:Propranolol / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
D000319:Adrenergic beta-Antagonists; D011433:Propranolol