Cardioprotective effect of carvedilol: inhibition of apoptosis in H9c2 cardiomyocytes via the TLR4/NF-κB pathway following ischemia/reperfusion injury

Abstract

Carvedilol is a non-selective β-blocker used in the treatment of cardiovascular disease, including myocardial ischemia. The aim of the present study was to investigate the molecular mechanisms underlying the effects of carvedilol on simulated ischemia/reperfusion (SI/R)-induced cardiomyocyte apoptosis in vitro. H9c2 cardiomyocytes were incubated with either a vehicle or an ischemic buffer during hypoxia followed by reoxygenation with or without carvedilol. In two additional groups, toll-like receptor 4 (TLR4) and nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) were inhibited by a TLR4 antibody and pyrrolidine dithiocarbamate, respectively. The results revealed that carvedilol markedly decreased SI/R-induced apoptosis in a concentration-dependent manner, as demonstrated by flow-cytometric analysis. This effect was shown to be associated with an increase in the B-cell lymphoma 2 (Bcl-2)/Bcl-2-associated X (Bax) protein ratio and concurrent reductions in the expression levels of TLR4 and NF-κB. These results suggest that carvedilol provides significant cardioprotection against SI/R-induced injury in H9c2 cardiomyocytes, an effect likely to be mediated through the TLR4/NF-κB signaling pathway.

Radioprotective 105 kDa protein attenuates ischemia/reperfusion-induced myocardial apoptosis and autophagy by inhibiting the activation of the TLR4/NF-κB signaling pathway in rats

“…Accumulating evidence indicates that apoptosis-and autophagy-associated myocyte death play key roles in the induction of MIRI (9,19,27). Our present study demonstrated that the overexpression of RP105 via a recombinant adenoviral vector is a promising cardioprotective strategy to induce anti-apoptotic and anti-autophagic effects in MIRI in vivo.…”

“…Herein, our data showed, for the first time to the best of our knowledge, that the TLR4, p-NF-κB/p65, and IL-6/ TNF-α signaling pathways were upregulated in MIRI, and therfore promoted apoptosis. These results, taken together with other findings (19,29), regarding the TLR4/NF-κB-IL-6 (TNF-α)-mediated apoptotic mechanism broaden our understanding of the multiple biological functions of TLR4, beyond being a canonical inflammatory sensor in MIRI.…”

“…Previous studies have shown that TLR4 plays a critical role as a pivotal sensor in inducing cell apoptosis during MIRI (19,20). By contrast, TLR4 deficiency markedly attenuates I/R-induced myocardial apoptosis (7).…”

“…Furthermore, blocking TLR4-induced apoptosis and autophagy may confer a protective effect against MIRI (5,7).Thus, a better understanding of the mechanisms which initiate apoptotic and autophagic responses is critical for the study of MIRI and for the development of novel treatments. TLR4, as an upstream common sensor of multiple intracellular pathways including TLR4/nuclear factor-κB (NF-κB) signaling, is commonly recognized as an important hallmark and potent stimulus of the apoptotic cascade as well as autophagic signaling (18)(19)(20). Previous findings have confirmed that TLR4 activity stimulated the downstream transcription factor NF-κB; it induced the expression of NF-κB target genes including interleukin (IL)-6 and tumor necrosis factor α (TNF-α), and led to the activation of the apoptotic cascade and autophagic responses (18).…”

Involvement of the TLR4/NF-κB Signaling Pathway in the Repair of Esophageal Mucosa Injury in Rats with Gastroesophageal Reflux Disease

“…A reduction in expression levels of TLR4 and NF-κB is an efficient way for carvedilol to inhibit ischemia/ reperfusion-induced apoptosis [36]. Taking all of our findings and previous findings together, we speculate that TLR4 activates the transcription of inflammation cytokines as well as proapoptotic signaling that results in cell death.…”