Abstract
Sepsis is a dysregulated systemic inflammatory response that often leads to cardiac dysfunction, which is termed sepsis-induced cardiomyopathy (SIC). Harmine, a natural β-carboline alkaloid compound, has been shown to exert pharmacological effects on several diseases. Here, we investigated whether harmine protected against SIC development and the underlying mechanisms. In vitro, the expression of the M1 phenotype markers iNOS and COX-2 was increased in RAW 264.7 cells stimulated with lipopolysaccharide (LPS), but this effect was reversed by the harmine intervention. Furthermore, LPS-induced increases in the levels of inflammatory cytokines, including IL-1β, IL-6, TNF-α, iNOS, COX-2, PGE2 and TXB2, generated by macrophages were suppressed when the cells were pretreated with harmine. Meanwhile, our findings showed that harmine administration effectively attenuated inflammation and apoptosis in H9c2 cells in the proinflammatory environment produced by macrophages, as evidenced by reductions in NLRP3 and cleaved caspase 3 levels and the p-NF-κB/NF-κB ratio. The western blot results indicated that the mechanisms underlying harmine-mediated inhibition of M1 polarization might be associated with suppression of STAT1/3, NF-κB and MAPK activation. Furthermore, an LPS injection induced cardiac dysfunction and decreased the survival rate of mice, which were alleviated by harmine treatment, and the relevant mechanism was possibly attributed to a drug-induced attenuation of the inflammatory and apoptotic processes in cardiomyocytes. Collectively, these results implied that harmine treatment protected against SIC by suppressing M1 phenotypic polarization and inflammation in macrophages.
Highlights
Sepsis is a systemic inflammatory response syndrome caused by various dysregulated responses to host infections, accompanied by life-threatening multiorgan dysfunction (Lelubre and Vincent, 2018)
We observed that the harmine intervention effectively alleviated cardiac dysfunction triggered by LPS-related sepsis in mice, and the relevant mechanism was attributed to drug-induced inhibition of macrophage polarization to the M1 phenotype and subsequent inflammation
Our findings revealed that the contents of iNOS and COX-2, which are key biomarkers of M1 macrophages, were increased following LPS insult, but these changes were abrogated by the administration of harmine in a dose-dependent manner, suggesting that harmine was capable of restraining the M1 phenotypic conversion of macrophages exposed to proinflammatory stimuli
Summary
Sepsis is a systemic inflammatory response syndrome caused by various dysregulated responses to host infections, accompanied by life-threatening multiorgan dysfunction (Lelubre and Vincent, 2018). To. Harmine Alleviated Sepsis-Induced Cardiomyopathy date, numerous researchers have attempted to decipher the mechanisms of SIC, and inflammation-related macrophages have been shown to play important roles in SIC development (Li et al, 2021). M1 macrophages exhibit a proinflammatory phenotype related to the host defense against pathogens, while M2 macrophages possess an anti-inflammatory phenotype related to inflammation resolution and tissue repair (Liu et al, 2014). When exposed to diverse stimuli, such as LPS, TNF-α and IFN-c, M1 macrophages are activated, and intracellular inflammatory and metabolic reprogramming pathways are activated, including STAT1, NF-κB and HIF-1α axes, eventually promoting the generation of plentiful cytokines that damage cardiomyocytes and induce cardiac dysfunction To date, the specific mechanisms responsible for SIC remain elusive
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