title: Exogenous heat shock cognate protein 70 pretreatment attenuates cardiac and hepatic dysfunction with associated anti-inflammatory responses in experimental septic shock.
abstract: It has been recently demonstrated that intracellular heat shock cognate protein 70 (HSC70) can be released into extracellular space with physiologic effects. However, its extracellular function in sepsis is not clear. In this study, we hypothesize that extracellular HSC70 can protect against lipopolysaccharide (LPS)-induced myocardial and hepatic dysfunction because of its anti-inflammatory actions. In Wistar rats, septic shock developed with hypotension, tachycardia, and myocardial and hepatic dysfunction at 4 h following LPS administration (10 mg/kg, i.v.). Pretreatment with recombinant bovine HSC70 (20 μg/kg, i.v.) attenuated LPS-induced hypotension and tachycardia by 21% and 23%, respectively (P < 0.05), improved myocardial dysfunction (left ventricular systolic pressure: 33%; max dP/dt: 20%; min dP/dt: 33%, P < 0.05), and prevented hepatic dysfunction (glutamic-oxaloacetic transaminase: 81 vs. 593 IU/L; glutamic-pyruvic transaminase: 15 vs. 136 IU/L, P < 0.05) compared with LPS-treated rats at 4 h. Heat shock cognate protein 70 also prevented LPS-induced hypoglycemia (217 vs. 59 mg/dL, P < 0.05) and elevated lactate dehydrogenase (1,312 vs. 6,301 IU/L, P < 0.05). Furthermore, HSC70 decreased LPS-induced elevation of circulating tumor necrosis factor α and nitrite/nitrate, and tissue expression of inducible nitric oxide synthase, cyclooxygenase 2, and matrix metalloproteinase 9 in the heart and liver. To investigate underlying mechanisms, we found that HSC70 attenuated LPS-induced nuclear translocation of nuclear factor κB subunit p65 by blocking the phosphorylation of inhibitor of nuclear factor κB. Finally, we showed that HSC70 repressed the activation of MAPKs caused by LPS. These results demonstrate that in LPS-induced septic shock, extracellular HSC70 conveys pleiotropic protection on myocardial, hepatic, and systemic derangements, with associated inhibition of proinflammatory mediators including tumor necrosis factor α, nitric oxide, cyclooxygenase 2, and matrix metalloproteinase 9, through mitogen-activated protein kinase/nuclear factor κB signaling pathways. Therefore, extracellular HSC70 may have a promising role in the prophylactic treatment of sepsis.
authors.affiliation: *Department of Paediatrics, Kaohsiung Medical University Hospital; and †Department of Paediatrics, Faculty of Medicine, ‡Department and Graduate Institute of Pharmacology, College of Medicine, Kaohsiung Medical University, Kaohsiung; and §Department of Pharmacy, Chia-Nan University of Pharmacy and Science, Tainan, Taiwan.
authors.forename: Jong-Hau
authors.initials: JH
authors.lastname: Hsu
authors.forename: Rei-Cheng
authors.initials: RC
authors.lastname: Yang
authors.forename: Shih-Jen
authors.initials: SJ
authors.lastname: Lin
authors.forename: Shu-Fen
authors.initials: SF
authors.lastname: Liou
authors.forename: Zen-Kong
authors.initials: ZK
authors.lastname: Dai
authors.forename: Jwu-Lai
authors.initials: JL
authors.lastname: Yeh
authors.forename: Jiunn-Ren
authors.initials: JR
authors.lastname: Wu
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D002417:Cattle; D019446:Endotoxemia / Q000378:metabolism; D005786:Gene Expression Regulation; D018840:HSP70 Heat-Shock Proteins / Q000494:pharmacology*; D006352:Heart Ventricles / Q000378:metabolism; D008070:Lipopolysaccharides / Q000737:chemistry; D008099:Liver / Q000201:enzymology / Q000503:physiopathology*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D009206:Myocardium / Q000201:enzymology; D009569:Nitric Oxide / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012772:Shock, Septic / Q000378:metabolism*; D051996:Transcription Factor RelA / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D018840:HSP70 Heat-Shock Proteins; D008070:Lipopolysaccharides; C498145:Rela protein, rat; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D020780:Matrix Metalloproteinase 9; C572337:Mmp9 protein, rat