Abstract
Lipopolysaccharide (LPS)-induced myocardial dysfunction is caused, at least in part, by mitochondrial dysfunction. Mitochondrial dysfunction and the oxidative damage associated with it are scavenged through various cellular defense systems such as autophagy to prevent harmful effects. Our recent study has demonstrated that cobalt protoporphyrin IX (CoPPIX), a potent inducer of heme oxygenase-1 (HO-1), ameliorates septic liver injuries by enhancing mitochondrial autophagy in rats. In our current study, we show that CoPPIX (5 mg/kg s.c.) not only accelerates the autophagic response but also promotes lysosome reformation in the rat heart treated with LPS (15 mg/kg i.p.). Lysosomal membrane-associated protein-2 (LAMP2), which is essential to the maintenance of lysosomal functions in the heart, is depleted transiently but restored rapidly during LPS administration in the rat. Activation of transcription factor EB (TFEB), a master regulator of lysosomal biogenesis and autophagy, was also observed, indicating a hyper consumption and subsequent reformation of the lysosome to meet the increased demand for autophagosome cleaning. CoPPIX was found to promote these processes and tended to restore the LPS-induced suppression of cardiac performances whilst chloroquine (CQ; 20 mg/kg i.p.), an inhibitor of lysosomes and autophagic protein degradation, abrogates these beneficial effects. The cardioprotective effect of CoPPIX against LPS toxicity was also observed via decreased levels of cardiac releasing enzymes in the plasma. Taken together, our current data indicate that lysosome reformation mediated by TFEB may be involved in cardioprotection against LPS-induced septic insults, and serve as a novel mechanism by which CoPPIX protects the heart against oxidative stress.
Highlights
Lipopolysaccharide (LPS), a major outer cell wall component of gram-negative bacteria, causes septic shock in humans and animals [1]
We examined the effects of cobalt protoporphyrin IX (CoPPIX) on the status of the mitochondria, autophagic response, and the lysosome in LPS-treated rat hearts
In the myocardium of LPS+CoPPIX-treated rat, some mitochondria seem to be degraded within the membranous structure (Fig. 2d), suggesting the autophagic elimination of damaged mitochondria
Summary
Lipopolysaccharide (LPS), a major outer cell wall component of gram-negative bacteria, causes septic shock in humans and animals [1]. The administration of LPS to laboratory animals leads to multi-organ dysfunction that includes myocardial depression [2,3,4]. Cardiac dysfunction is caused by the production of proinflammatory cytokines, mitochondrial dysfunction, and subsequent contractile failure followed by a precipitous drop in cardiac output [2,3,5]. Autophagy has been shown to play pivotal roles in the elimination of dysfunctional mitochondria [6]. Following their elimination, dysfunctional mitochondria should be replaced to ensure that normal cellular functions are not affected. Transient mitochondrial depletion followed by regeneration by these factors has been demonstrated in the hearts of LPS-treated animals as well as in cultured cardiomyocytes [9,10,11]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
