ENDOGENOUS β3-ADRENERGIC RECEPTOR ACTIVATION ALLEVIATES SEPSIS-INDUCED CARDIOMYOCYTE APOPTOSIS VIA PI3K/AKT SIGNALING PATHWAY

beta(3)-adrenergic receptor (beta(3)-AR) has been proposed as a new therapy for several myocardial diseases. However, the effect of beta(3)-AR activation on sepsis-induced myocardial apoptosis is unclear. Here, we investigated the effect of beta(3)-AR activation on the cardiomyocyte apoptosis and cardiac dysfunction in cecal ligation and puncture (CLP)-operated rats and lipopolysaccharide (LPS)-treated cardiomyocytes. We found that beta(3)-AR existed both in adult rat ventricular myocytes (ARVMs) and H9c2 cells. The expression of beta(3)-AR was upregulated in LPS-treated ARVMs and the heart of CLP rats. Pretreatment with beta 3-AR agonist, BRL37 344, inhibited LPS-induced cardiomyocyte apoptosis and caspase-3, -8, and -9 activation in ARVMs. BRL37344 also reduced apoptosis and increased the protein levels of PI3K, p-Akt(Ser473) and p-eNOS(Ser1177) in LPS-treated H9c2 cells. Inhibition of PI3K using LY294002 abolished the inhibitory effect of BRL37344 on LPS-induced caspase-3, -8, and -9 activation in H9c2 cells. Furthermore, administration of beta 3-AR antagonist, SR59230A (5 mg/kg), significantly decreased the maximum rate of left ventricular pressure rise (+dP/dt) in CLP-induced septic rats. SR59230A not only increased myocardial apoptosis, reduced p-Akt(Ser473) and Bcl-2 contents, but also increased mitochondrial Bax, cytoplasm cytochrome c, cleaved caspase-9, and cleaved caspase-3 levels of the myocardium in septic rats. These results suggest that endogenous beta(3)-AR activation alleviates sepsis-induced cardiomyocyte apoptosis via PI3K/Akt signaling pathway and maintains intrinsic myocardial systolic function in sepsis.