title: Endogenous glucocorticoids inhibit myocardial inflammation induced by lipopolysaccharide:  involvement of regulation of histone deacetylation.
abstract: Emerging evidence indicates that myocardial inflammation plays a key role in the pathogenesis of cardiac diseases. But the exact mechanisms for this chronic inflammatory disorder have not been elucidated. Glucocorticoids (GCs) are the most effective anti-inflammatory treatments available for many inflammatory diseases. However, it is unknown whether endogenous GCs are able to exert anti-inflammatory effect on myocardial inflammation. In this study, the potential role of endogenous GCs in the regulation of myocardial inflammation was investigated. We showed that the reduction of endogenous GC level by adrenalectomy promoted the production of basal and lipopolysaccharide (LPS)-induced proinflammatory cytokines, which could be partly reversed by supplementing with exogenous physiological level of hydrocortisone. Inhibition of GC receptor (GR) signaling pathway with GR antagonist mifepristone (RU486) or histone deacetylase inhibitor trichostatin A (TSA) also increased the levels of basal and LPS-induced proinflammatory cytokines. Moreover, blockade of GC-GR signaling pathway by adrenalectomy, RU486 or TSA enhanced LPS-induced myocardial nuclear factor-κB activation and histone acetylation but inhibited myocardial histone deacetylase expression and activity. Cardiac function studies demonstrated that blockade of the GC-GR signaling pathway aggravated inflammation-induced cardiac dysfunction. These findings indicate that endogenous GCs are able to inhibit myocardial inflammation induced by LPS. Endogenous GCs represent an important endogenous anti-inflammatory mechanism for myocardium in rats and such mechanism injury may be an important factor for pathogenesis of cardiac diseases.
authors.affiliation: Department of Pharmacology, Guangzhou Medical University, Guangzhou, China.
authors.forename: Hai-Ning
authors.initials: HN
authors.lastname: Zhang
authors.forename: Yan-Hua
authors.initials: YH
authors.lastname: He
authors.forename: Gen-Shui
authors.initials: GS
authors.lastname: Zhang
authors.forename: Miao-Shan
authors.initials: MS
authors.lastname: Luo
authors.forename: Yue
authors.initials: Y
authors.lastname: Huang
authors.forename: Xiao-qian
authors.initials: XQ
authors.lastname: Wu
authors.forename: Shi-Ming
authors.initials: SM
authors.lastname: Liu
authors.forename: Jian-Dong
authors.initials: JD
authors.lastname: Luo
authors.forename: Min-Sheng
authors.initials: MS
authors.lastname: Chen
mesh_terms: D000818:Animals; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005938:Glucocorticoids / Q000378:metabolism*; D006655:Histone Deacetylases / Q000378:metabolism; D006854:Hydrocortisone / Q000008:administration & dosage / Q000378:metabolism; D006877:Hydroxamic Acids / Q000494:pharmacology; D007249:Inflammation / Q000503:physiopathology*; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D015735:Mifepristone / Q000494:pharmacology; D009206:Myocardium / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D016207:Cytokines; D005938:Glucocorticoids; D006877:Hydroxamic Acids; D008070:Lipopolysaccharides; D011965:Receptors, Glucocorticoid; D015735:Mifepristone; C012589:trichostatin A; D006655:Histone Deacetylases; D006854:Hydrocortisone