Liver X receptor agonist T0901317 ameliorates sepsis-induced myocardial injury and dysfunction: the role of SIRT1 signaling
Han Dong1 2 Chen Jiangwei1 2 Cao Feng1 2
1.Department of Cardiology, State Key Laboratory of Kidney Diseases, Chinese PLA General Hospital, Beijing, China 100853
2.Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi’an 710032, China
Objectives: Sepsis patients suffering from cardiac dysfunction experience a 70–90 % mortality rate, which is overwhelmingly higher than those without cardiac dysfunction of only 20 %. In this regard, it is pertinent to develop novel therapeutic strategy dealing with sepsis-induced myocardial injury and dysfunction in order to improve the outcome of sepsis patients. Liver X receptor (LXR) was recently reported to protect liver and lung against septic injury. However, studies addressing the effects of LXR activation on septic heart injury are still lacking.
Methods: Male cardiac-specific SIRT1 knockout mice (SIRT1−/− ) mice and their wild-type littermates were subjected to sepsis by cecal ligation and puncture (CLP). LXR agonist T0901317 was administrated intraperitoneally (30 mg/kg). The survival rate of mice was recorded in the 7-day period post CLP. Left ventricular functional analysis with non-invasive echocardiography and invasive hemodynamic assessment were performed on post-operational day 2(POD2) to evaluate cardiac function. Morphological changes of myocardial tissues were observed by H&E staining under a light microscopy. Myocardial apoptosis was evaluated by a TUNEL assay kit. Biochemical indices of heart injury including serum AST, LDH, CK and CK-MB using commercially available assay kits following the manufacturer’s instructions. Myocardial endoplasmic-reticulum(ER) stress (protein level of CHOP, GRP78, GRP94, IRE1α, and ATF6) were assessed by both Western Blot and immunohistochemical staining. SIRT1 signal and its substrates were also detected by Western Blot
Results: Our data showed that LXR agonist protected against CLP-induced myocardial injury and dysfunction, as evidenced by improved myocardial morphological changes, improved hypotension, reduced serum concentration of biochemical indices of heart injury (AST, LDH, CK and CK-MB), and elevation of cardiac functional parameters(LVEF 55.6±2.2% vs. 64.1±3.4%, respectively, N=11-14, p=0.0005). Furthermore, we found that LXR agonist reduced the level of inflammatory cytokines, such as TNF-α, IL-1β, IL-6 and HMGB1, the overproduction of ROS and MDA, and the accumulation of endoplasmic-reticulum stress. Additionally, LXR agonist increases the activity of antioxidant enzymes, such as SOD, GPx, and CAT. However, these aforementioned beneficial actions of LXR agonist administration following CLP was abolished in cardiac specific SIRT1 KO mice, suggesting the protective effects of LXR agonist is associated with SIRT1 signaling activation. Western Blot analysis of SIRT1 signal and its substrates further revealed that T0901317 enhanced SIRT1 signaling and subsequent deacetylation and activation of anti-oxidative FoxO1 and anti-ER stress HSF1, deacetylation and inhibition of pro-inflammatory NF-kB and pro-apoptotic P53, thereby alleviating sepsis-induced myocardial injury and dysfunction.
Conclusions: In conclusion, our current work demonstrated a beneficial role of LXR agonist in septic murine heart mainly through attenuating oxidative stress, endoplasmic-reticulum stress, inflammation, and apoptosis. Furthermore, by employing SIRT1−/− mice, we demonstrated that the beneficial actions of LXR agonist in septic heart were possibly associated with activation of SIRT1 signaling and subsequent deacetylation and activation of FoxO1 and HSF1, as well as deacetylation and inhibition of NF-kB and P53. Those findings may guide the prospective clinical trial to evaluate the latent therapeutic effect of LXR agonist for patients with sepsis.