Propranolol enhances cell cycle-related gene expression in pressure overloaded hearts

Department of Pharmacology, National Institute of Health, Rome, Italy.
British Journal of Pharmacology (Impact Factor: 4.84). 05/2011; 164(8):1917-28. DOI: 10.1111/j.1476-5381.2011.01504.x
Source: PubMed


Cell cycle regulators are regarded as essential for cardiomyocyte hypertrophic growth. Given that the β-adrenoceptor antagonist propranolol blunts cardiomyocyte hypertrophic growth, we determined whether propranolol alters the expression of cell cycle-related genes in mouse hearts subjected to pressure overload.
Pressure overload was induced by transverse aortic constriction (TAC), whereas the expression levels of 84 cell cycle-related genes were assayed by real-time PCR. Propranolol (80 mg·kg(-1) ·day(-1) ) was administered in drinking water for 14 days.
Two weeks after surgery, TAC caused a 46% increase in the left ventricular weight-to-body weight (LVW/BW) ratio but no significant changes in cell cycle gene expression. Propranolol, at plasma concentrations ranging from 10 to 140 ng·mL(-1) , blunted the LVW/BW ratio increase in TAC mice, while significantly increasing expression of 10 cell cycle genes including mitotic cyclins and proliferative markers such as Ki67. This increase in cell cycle gene expression was paralleled by a significant increase in the number of Ki67-positive non-cardiomyocyte cells as revealed by immunohistochemistry and confocal microscopy. β-Adrenoceptor signalling was critical for cell cycle gene expression changes, as genetic deletion of β-adrenoceptors also caused a significant increase in cyclins and Ki67 in pressure overloaded hearts. Finally, we found that metoprolol, a β(1) -adrenoceptor antagonist, failed to enhance cell cycle gene expression in TAC mice.
Propranolol treatment enhances cell cycle-related gene expression in pressure overloaded hearts by increasing the number of cycling non-cardiomyocyte cells. These changes seem to occur via β(2) -adrenoceptor-mediated mechanisms.

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    • "Propranolol has been shown to affect the expression of cyclins across multiple cell types (5,23), gluconeogenic and glycolytic enzymes in the liver (24), epidermal growth factor 1 in cardiomyocytes (25) and pigment epithelial derived factor in the retina (26). However, these studies have focused on small subsets of genes and did not look at large-scale changes in genomic expression patterns. "
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