Intermittent beta-adrenergic blockade downregulates the gene expression of beta-myosin heavy chain in the mouse heart

Expression of the beta-myosin heavy chain (beta-MHC), a major component of the cardiac contractile apparatus, is tightly regulated as even modest increases can be detrimental to heart under stress. In healthy hearts, continuous inhibition of beta-adrenergic tone upregulates beta-MHC expression. However, it is unknown whether the duration of the beta-adrenergic inhibition and beta-MHC expression are related. Here, we evaluated the effects of intermittent beta-blockade on cardiac beta-MHC expression. To this end, the beta-blocker propranolol, at the dose of 15mg/kg, was administered once a day in mice for 14 days. This dosing schedule caused daily drug-free periods of at least 6 h as evidenced by propranolol plasma concentrations and cardiac beta-adrenergic responsiveness. Under these conditions, beta-MHC expression decreased by about 75% compared to controls. This effect was abolished in mice lacking beta 1-but not beta 2-adrenergic receptors (beta-AR) indicating that beta-MHC expression is regulated in a beta 1-AR-dependent manner. In beta 1-AR knockout mice, the baseline beta-MHC expression was fourfold higher than in wild-type mice. Also, we evaluated the impact of intermittent beta-blockade on beta-MHC expression in mice with systolic dysfunction, in which an increased beta-MHC expression occurs. At 3 weeks after myocardial infarction, mice showed systolic dysfunction and upregulation of beta-MHC expression. Intermittent beta-blockade decreased beta-MHC expression while attenuating cardiac dysfunction. In vitro studies showed that propranolol does not affect beta-MHC expression on its own but antagonizes catecholamine effects on beta-MHC expression. In conclusion, a direct relationship occurs between the duration of the beta-adrenergic inhibition and beta-MHC expression through the beta 1-AR.