title: Activation of AMP-activated protein kinase reduces collagen production via p38 MAPK in cardiac fibroblasts induced by coxsackievirus B3.
abstract: Collagen deposition is the major cause of myocardial fibrosis, contributing to impaired cardiac contractile function in coxsackie virus B3 (CVB3)-infected hearts. Adenosine monophosphate-activated protein kinase (AMPK) has been considered as a cellular fuel gauge and super metabolic regulator, however, whether AMPK has an effect on collagen production in CVB3‑infected heart remains to be elucidated. In the present study, the association between AMPK activation and CVB3‑infected neonatal rat cardiac fibroblasts (NRCFs) was investigated. Collagen production was determined by the hydroxyproline content of the supernatant and by the expression of type I/IV collagen in the cell lysate. Rat hydroxyproline ELISA was used to detect hydroxyproline content in the supernatant. The expression of type I/IV collagen, and the phosphorylation of AMPKα‑Thr172 and p38 in the cell lysate were evaluated using western blotting. As expected, it was found that the hydroxyproline content in the supernatant, and the production of collagen I/IV in the cell lysate were significantly promoted at 48 h post‑CVB3‑infection. However, this effect was inhibited in a dose‑dependent manner when pretreated with 5‑aminoimidazole‑4‑carboxamide‑1‑4‑ribofuranoside (AICAR) for 2 h prior to CVB3‑infection. However, if the cells were preincubated with compound C or SB203580 for 30 min prior the treatment with AICAR, the inhibitive effects of AICAR were reversed. The results of the western blotting indicated that the phosphorylation of AMPKα‑Thr172 and p38 were significantly increased by AICAR in the NRCFs. However, only the phosphorylation of p38 mitogen‑activated protein kinase (MAPK) was inhibited by SB203580. In conclusion, AMPK activation reduced collagen production via the p38 MAPK‑dependent pathway in the cardiac fibroblasts induced by CVB3. The results of the present study may contribute to identifying an effective therapy for CVB3‑induced myocarditis and CVB3-associated dilated cardiomyopathy.
authors.affiliation: Department of Cardiology, The Third Affiliated Hospital of Nantong University, Wuxi Institute of Integrated Traditional Chinese and Western Medicine, Wuxi, Jiangsu 214041, P.R. China.
authors.forename: Shengyang
authors.initials: S
authors.lastname: Jiang
authors.affiliation: Clinical Central Laboratory, The Third Affiliated Hospital of Nantong University, Wuxi Institute of Integrated Traditional Chinese and Western Medicine, Wuxi, Jiangsu 214041, P.R. China.
authors.forename: Donglin
authors.initials: D
authors.lastname: Jiang
authors.affiliation: Clinical Central Laboratory, The Third Affiliated Hospital of Nantong University, Wuxi Institute of Integrated Traditional Chinese and Western Medicine, Wuxi, Jiangsu 214041, P.R. China.
authors.forename: Peng
authors.initials: P
authors.lastname: Zhao
authors.affiliation: Clinical Central Laboratory, The Third Affiliated Hospital of Nantong University, Wuxi Institute of Integrated Traditional Chinese and Western Medicine, Wuxi, Jiangsu 214041, P.R. China.
authors.forename: Xinlong
authors.initials: X
authors.lastname: He
authors.affiliation: Department of Geratology, Tianjin Geriatric Institute, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China.
authors.forename: Shunli
authors.initials: S
authors.lastname: Tian
authors.affiliation: Department of Cardiology, The Third Affiliated Hospital of Nantong University, Wuxi Institute of Integrated Traditional Chinese and Western Medicine, Wuxi, Jiangsu 214041, P.R. China.
authors.forename: Xueming
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of Cardiology, The Third Affiliated Hospital of Nantong University, Wuxi Institute of Integrated Traditional Chinese and Western Medicine, Wuxi, Jiangsu 214041, P.R. China.
authors.forename: Yijia
authors.initials: Y
authors.lastname: Tao
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism*; D029822:Enterovirus B, Human / Q000502:physiology*; D004789:Enzyme Activation; D006367:HeLa Cells; D006801:Humans; D058628:Myofibroblasts / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology* / Q000821:virology; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D047428:Protein Kinase Inhibitors; D003094:Collagen; D048051:p38 Mitogen-Activated Protein Kinases; D055372:AMP-Activated Protein Kinases