Lipopolysaccharide (LPS), a constituent of the outer membrane of Gram-negative bacteria, is the principal culprit factor responsible for the development of multi-organ failure including septic heart failure - a major contributor to increased mortality in patients with sepsis. However, there is still no efficacious treatment for septic cardiomyophathy. ALDH2 is well-known for its distinct beneficial role in cardiac pathologies including heart failure, ischemia and reperfusion injury. Little is known with regards to its effect on septic cardiomyopathy and the underlying mechanism. This study was designed to examine whether ALDH2 affects LPS-induced myocardial dysfunction and the underlying mechanism involved with a focus on ER stress and autophagy. WT and ALDH2 transgenic mice were subjected to LPS (4 mg/kg, 4 h). Myocardial mechanical and intracellular Ca2+ properties were examined in FVB wild-type and ALDH2 transgenic mice using echocardiography and IonOptix SoftEdge techniques. Protein markers for ER stress, autophagy and related signaling molecules were evaluated. LPS compromised cardiac contractile function shown as reduced fractional shortening, peak shortening, maximal velocity of shortening/relengthening, prolonged relengthening duration and impaired intracellular Ca2+ homeostasis, associated with overt ER stress, upregulated autophagy, suppressed phosphorylation of Akt and its downstream signal molecule mTOR, the effects of which were attenuated by ALDH2. In vitro study revealed that the ER stress inducer tunicamycin exacerbated LPS-induced myocardial dysfunction, which was abrogated by the ALDH2 activator Alda-1 and the autophagy inhibitor 3-MA. Interestingly, the beneficial effect of Alda-1 was obliterated by the autophagy inducer rapamycin, Akt inhibitor AktI and mTOR inhibitor RAD001. We conclude that ALDH2 protects against LPS-induced myocardial dysfunction possibly through suppression of ER stress and inhibition of autophagy.
ABSTRACT The family with sequence similarity 3 (FAM3) gene family is a cytokine-like gene family with four members FAM3A, FAM3B, FAM3C and FAM3D. In this study, we found that FAM3D strongly chemoattracted human peripheral blood neutrophils and monocytes. To identify the FAM3D receptor, we used chemotaxis, receptor internalization, Ca2+ flux and radioligand-binding assays in FAM3D-stimulated HEK293 cells that transiently expressed formyl peptide receptor (FPR)1 or FPR2 to show that FAM3D was a high affinity ligand of these receptors, both of which were highly expressed on the surface of neutrophils, and monocytes and macrophages. After being injected into the mouse peritoneal cavity, FAM3D chemoattracted CD11b+ Ly6G+ neutrophils in a short time. In response to FAM3D stimulation, phosphorylated ERK1/2 and phosphorylated p38 MAPK family proteins were upregulated in the mouse neutrophils, and this increase was inhibited upon treatment with an inhibitor of FPR1 or FPR2. FAM3D has been reported to be constitutively expressed in the gastrointestinal tract. We found that FAM3D expression increased significantly during colitis induced by dextran sulfate sodium. Taken together, we propose that FAM3D plays a role in gastrointestinal homeostasis and inflammation through its receptors FPR1 and FPR2.
Background and objective. A variety of cytokines are involved in the incidence and development of bronchial asthma. This study was designed to reveal the relationship among genetic polymorphism of cytokine genes, expression levels of cytokines and incidence of bronchial asthma. Methods. We analyzed 14 single nucleotide polymorphism loci in the 10 major cytokine genes plus plasma protein levels of 7 proteins in the bronchial asthma patients (n = 108) and the healthy population (n = 88) of the Han people in northern China. The polymorphism-based genotypes were identified by the sequence-specific primer-polymerase chain reaction. The plasma protein levels were determined by enzyme-linked immunoassay. Bioinformatics analysis was applied to further data processing.Results. Data presented here showed that the 6 polymorphism loci were significantly correlated with the incidence of asthma (p < 0.05). Two of them, IL-2 (−330) and IL-2 (+166), constituted a linkage disequilibrium block. The GG haplotype of this block gave a relatively higher correlation with asthma (p = 0.0767). The plasma protein levels of IgE, IL-6 and IL-1 β correlated with a number of polymorphism loci tested (p < 0.05), of which IgE gave the most significant correlation. The plasma IL-10 and IL-12 levels of the patients in the asthma group were significantly lower than those of the healthy adults in the control group (p < 0.05), while IgE gave the opposite result (p < 0.0001). We constructed a prototype of the metabolic and regulatory network composed of bronchial asthma-related proteins. In this network, IL-6 and TNF-α, were found with a high degree (D = 343 and 235, respectively) and IL-1β with a moderate degree of connection (D = 155). Conclusions.We have found that various degrees of correlation with cytokine genes and protein expression of single nucleotide polymorphism in bronchial asthma. IL-6 and IL-1β appear to play important biological roles in the pathogenesis of asthma. During the analysis of correlation between genetic polymorphism and a complex disease, the effects of environmental factors should be taken into account. The information at the protein level should be fully developed and the bioinformatics techniques can be used for the comprehensive analysis, to have a deep understanding of molecular mechanisms of incidence and development of diseases.
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