- Authors: Bogush N. et al.
- Year: 2022
- Journal: Sci Rep 12 8852
- Applications: in vivo / siRNA / in vivo-jetPEI
β1-AR-specific siRNA or scrambled siRNA (control) was administered using in vivo-jetPEI. β1-AR siRNA (100 ng) was dissolved in 1 ml of the in vivo-jetPEI:10% glucose mixture and was injected 100 μl per mouse via i.p. route (10 ng/mouse). β1-AR siRNA was a pool of 2 different siRNA duplexes.
Renewal of the myocardium by preexisting cardiomyocytes is a powerful strategy for restoring the architecture and function of hearts injured by myocardial infarction. To advance this strategy, we show that combining two clinically approved drugs, but neither alone, muscularizes the heart through cardiomyocyte proliferation. Specifically, in adult murine cardiomyocytes, metoprolol, a cardioselective β1-adrenergic receptor blocker, when given with triiodothyronine (T3, a thyroid hormone) accentuates the ability of T3 to stimulate ERK1/2 phosphorylation and proliferative signaling by inhibiting expression of the nuclear phospho-ERK1/2-specific phosphatase, dual-specificity phosphatase-5. While short-duration metoprolol plus T3 therapy generates new heart muscle in healthy mice, in mice with myocardial infarction-induced left ventricular dysfunction and pathological remodeling, it remuscularizes the heart, restores contractile function and reverses chamber dilatation; outcomes that are enduring. If the beneficial effects of metoprolol plus T3 are replicated in humans, this therapeutic strategy has the potential to definitively address ischemic heart failure.