title: Radioprotective 105 kDa protein attenuates ischemia/reperfusion-induced myocardial apoptosis and autophagy by inhibiting the activation of the TLR4/NF-κB signaling pathway in rats.
abstract: Toll-like receptor 4 (TLR4) serves as an important inducer of apoptotic and autophagic responses in myocardial ischemia/reperfusion (I/R) injury (MIRI). Radioprotective 105 kDa protein (RP105) is a specific inhibitor of TLR4. However, the molecular mechanisms by which RP105 represses myocardial apoptosis and autophagy through TLR4‑mediated signaling during I/R have not yet been fully elucidated. Therefore, in the present study, we aimed to examine whether adenovirus-mediated RP105 overexpression repressed myocardial apoptosis and autophagy by inhibiting the TLR4-driven mechanism in MIRI. Three days after the injection of virus or saline into the myocardium, Sprague-Dawley (SD) rats were subjected to 30 min of left anterior descending coronary artery occlusion and 6 h of reperfusion. Myocardial specimens were prepared for analysis. We performed immunohistochemichal and histopathological analysis, the measurement of cardiac biomarkers, TUNEL assay , RT-qPCR and western blot analysis. The results indicated that the overexpression of RP105 contributed to an amelioration of myocardial histological damage, decreased leakage of creatine kinase (CK) and lactate dehydrogenase (LDH), as well as a reduction in the number of TUNEL-positive cardiomyocytes. The levels of positively associated modulators of apoptosis and autophagy were also significantly downregulated by RP105, whereas Bcl-2, which plays an opposite role in inducing apoptosis and autophagy, was inversely upregulated. Furthermore, the overexpression of RP105 led to the repression of TLR4 activity and the phosphorylation of NF-κB/p65, as well as the reduced production of the cytokines interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α). Taken together, these data suggest that RP105 protects the myocardium against apoptosis and autophagy, and plays a cardioprotective role during I/R injury. This is most likely due to the inactivation of TLR4/NF-κB signaling pathway. Thus, RP105 may represent an innovative therapeutic target for attenuating MIRI.
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, Cardiovascular Research Institute of Wuhan University, Hubei Key Laboratory of Cardiology, Wuhan, Hubei 430060, P.R. China.
authors.forename: Xin
authors.initials: X
authors.lastname: Guo
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, Cardiovascular Research Institute of Wuhan University, Hubei Key Laboratory of Cardiology, Wuhan, Hubei 430060, P.R. China.
authors.forename: Hong
authors.initials: H
authors.lastname: Jiang
authors.affiliation: Institute of Cardiovascular Diseases, China Three Gorges University, Yichang, Hubei 443000, P.R. China.
authors.forename: Jun
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, Cardiovascular Research Institute of Wuhan University, Hubei Key Laboratory of Cardiology, Wuhan, Hubei 430060, P.R. China.
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.affiliation: Institute of Cardiovascular Diseases, China Three Gorges University, Yichang, Hubei 443000, P.R. China.
authors.forename: Jian
authors.initials: J
authors.lastname: Yang
authors.affiliation: Institute of Cardiovascular Diseases, China Three Gorges University, Yichang, Hubei 443000, P.R. China.
authors.forename: Jia-Wang
authors.initials: JW
authors.lastname: Ding
authors.affiliation: Institute of Cardiovascular Diseases, China Three Gorges University, Yichang, Hubei 443000, P.R. China.
authors.forename: Song
authors.initials: S
authors.lastname: Li
authors.affiliation: Institute of Cardiovascular Diseases, China Three Gorges University, Yichang, Hubei 443000, P.R. China.
authors.forename: Hui
authors.initials: H
authors.lastname: Wu
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, Cardiovascular Research Institute of Wuhan University, Hubei Key Laboratory of Cardiology, Wuhan, Hubei 430060, P.R. China.
authors.forename: Hua-Sheng
authors.initials: HS
authors.lastname: Ding
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D017209:Apoptosis; D001343:Autophagy; D015153:Blotting, Western; D003402:Creatine Kinase / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D008856:Microscopy, Fluorescence; D015428:Myocardial Reperfusion Injury / Q000235:genetics / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D051996:Transcription Factor RelA / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D015703:Antigens, CD; C000615712:Cd180 protein, rat; D015850:Interleukin-6; D051197:Toll-Like Receptor 4; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D003402:Creatine Kinase