Abstract
Shikonin (SHI) is an anti-inflammatory agent extracted from natural herbs. It is still unknown whether SHI ameliorates lipopolysaccharide (LPS)-induced cardiac dysfunction. This study aims to explore the protective effects of SHI on LPS-induced myocardial injury and its mechanism. The LPS-induced cardiac dysfunction mouse model was employed to investigate the protective effects of SHI. In the present study, we found that SHI treatment improved the survival rate and cardiac function and remarkably ameliorated the release of inflammatory cytokines and macrophage infiltration in heart tissue of LPS-treated mice. SHI also reduced lactate dehydrogenase (LDH) and cardiac troponin (cTn) release, cell inflammation, and apoptosis in LPS plus adenosine triphosphate (ATP)-treated H9c2 cells. In addition, SHI significantly upregulated silent information regulator 1 (SIRT1) expression and suppressed the upregulation of NOD-like receptor protein 3 (NLRP3), cleaved caspase-1, and caspase-1 activity in heart tissues induced by LPS. Meanwhile, we got the same results in LPS plus ATP-treated H9c2 cells in vitro. Further, SIRT1 inhibitor or siRNA partially blocked SHI-mediated upregulation of SIRT1 expression and downregulation of NLRP3, cleaved caspase-1, and caspase-1 activity in heart tissues induced by LPS. Therefore, we conclude that SHI ameliorates LPS-induced cardiac dysfunction by inhibiting SIRT1-dependent activation of NLRP3 inflammasomes and might be a promising therapeutic strategy for the treatment of LPS-induced cardiac dysfunction.
Highlights
Cardiac dysfunction is a common complication of severe sepsis, which represents one of the leading causes of death in intensive care units (Court et al, 2002; Narvaez et al, 2018)
Shikonin Improves Survival and Ameliorates Cardiac Dysfunction in Lipopolysaccharide-Treated Mice. It is still unknown whether SHI presents any protective efficacy on cardiac dysfunction induced by LPS
Echocardiography evaluation revealed that ejection fraction (EF) and fractional shortening (FS) were significantly reduced by LPS, while SHI treatment reversed the decreased effects on EF and FS induced by LPS (Figures 1B,C)
Summary
Cardiac dysfunction is a common complication of severe sepsis, which represents one of the leading causes of death in intensive care units (Court et al, 2002; Narvaez et al, 2018). Uncontrolled immune and inflammatory responses were involved in the main mechanisms of sepsis-induced cardiac dysfunction (SICD) (Kakihana et al, 2016; Liu et al, 2017). LPS stimulation resulted in the central inflammatory response and triggered rapid inflammasome activation, which included NOD-like receptor protein 3 (NLRP3), caspase-1, and apoptosis-associated speck-like protein (ASC). In these processes, inflammasome sensors recruited ASC to generate a caspase-1-activating platform and promote the maturation of pro-inflammatory cytokines, interleukin-1β (IL-1β) and IL-18 (Abderrazak et al, 2015; Karki and Kanneganti, 2019). Activation of SIRT1-dependent pathways has become a promising therapeutic strategy for the treatment of SICD
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