Introduction: Caspase activation and cardiomyocyte apoptosis have been implicated in lipopolysaccharide (LPS)-induced cardiac contractile dysfunction. We have recently demonstrated that β1-adrenoceptor (AR) activation by endogenous norepinephrine contributes to cardiomyocyte apoptosis in endotoxemic mice. Here, we further investigated the molecular mechanisms for the enhancing effect of β₁-AR activation on LPS-induced cardiomyocyte apoptosis. Methods: The adult mouse ventricular myocytes were exposed to LPS, dobutamine, protein kinase A (PKA) inhibitor or/and nifedipine, an L-type Ca²⁺ channel blocker. Male BALB/c mice were treated with LPS or/ and β₁-AR antagonist, atenolol. Cardiomyocyte apoptosis was determined by terminal deoxynucleotidyl transferase-mediated dUTP nick-end-labeling (TUNEL) assay and apoptosis-associated molecules were detected. Results: LPS induced apoptosis in adult mouse ventricular myocytes, dobutamine (DOB), a β₁-AR agonist, promoted apoptosis, caspase-8, 9 and 3 activation and increased cytosolic Ca²⁺ concentration in LPS-challenged cardiomyocytes. DOB also up-regulated TNF-α expression, decreased Bcl-2 levels, promoted Bax translocation to mitochondria, mitochondrial membrane potential loss and cytochrome c release as well as IκBα, p38 MAPK, JNK and Ca²⁺/calmodulin-dependent protein kinase II (CaMKII) phosphorylation in LPS-treated cardiomyocytes. PKA inhibitor abolished the effects of DOB on caspase-9 activation, Bcl-2 levels as well as JNK and p38 MAPK phosphorylation, but not on IκBα phosphorylation, TNF-α expression and caspase-8 activation in LPS-stimulated cardiomyocytes. Pretreatment with nifedipine not only significantly blocked the enhancing effects of DOB on LPS-induced elevation in cytosolic Ca²⁺ concentration and CaMKII phosphorylation in cardiomyocytes, but also partly reversed the effects of DOB on caspase-9 and caspase-3/7 activities in LPS-treated cardiomyocytes. Furthermore, atenolol suppressed TNF-α expression, JNK, p38 MAPK and CaMKII phosphorylation, increased Bcl-2 expression, and inhibited cytochrome c release and cardiomyocyte apoptosis in the myocardium of endotoxemic mice. Conclusions: β₁-AR activation promotes LPS-induced apoptosis through activating PKA, increasing CaMKII phosphorylation as well as enhancing IκBα phosphorylation and TNF-α expression in cardiomyocytes.

Neural stem cells (NSCs) hold great potential for the treatment of Alzheimer’s disease (AD) through both cellular replacement and their secretion of trophic factors. Lycopene is a potent β‐carotenoid antioxidant that has been shown to ameliorate oxidative damage in previous studies. However, it is unclear if lycopene can interact with NSCs to induce the secretion of growth factors, and whether pretreatment with lycopene will allow NSCs to secrete enough trophic factors to reduce oxidative damage to neurons. We pretreated cultured NSCs with lycopene, then applied the lycopene‐treated‐NSC‐conditioned media (Ly‐NSC‐CM) to primary neuronal cultures exposed to tert‐butyl hydroperoxide (t‐BHP) to induce oxidative damage. We found that lycopene promoted the secretion of nerve growth factor (NGF), brain‐derived neurotrophic factor (BDNF), and vascular endothelial growth factor (VEGF) from NSCs. In addition, Ly‐NSC‐CM attenuated oxidative stress and reduced t‐BHP‐induced cell apoptosis. We found an antiapoptotic effect related to inhibited expression of Bax/Bcl‐2, cytochrome C, and cleaved caspase‐3. Moreover, Ly‐NSC‐CM increased the levels of synaptic proteins, including synaptophysin (SYP) and postsynaptic density 95 (PSD‐95), and activated the PI3K/Akt pathway in cultured neurons. Collectively, these data indicate that Ly‐NSC‐CM could protect neurons from t‐BHP‐induced oxidative damage.