title: Involvement of AMPK and MAPK signaling during the progression of experimental autoimmune myocarditis in rats and its blockade using a novel antioxidant.
abstract: There are various reports suggesting the role of angiotensin (Ang) receptor blockers, Ang converting enzyme inhibitors, calcium channel blockers, diuretics and antioxidants against the progression of experimental autoimmune myocarditis (EAM) to dilated cardiomyopathy (DCM). Most of them were reported to be effective during this adverse cardiac remodeling. Recently much attention has been paid to studying the involvement of AMP-activated protein kinase (AMPK) and mitogen activated protein kinase (MAPK) in various cardiovascular ailments. AMPK acts as a master sensor of cellular energy balance via maintenance of lipid and glucose metabolism. Evidences also suggest the relation between AMPK and oxidative stress during physiological and pathological myocardial cellular function. Since, it is of interest to identify the roles of AMPK and MAPK during the progression of EAM to DCM and also the effect of edaravone, a novel free radical scavenger, against its progression. For this, we have carried out western blotting, histopathological staining and immunohistochemical analyses to measure the myocardial expressions of AMPK signaling and oxidative stress related parameters in normal and vehicle or edaravone-treated EAM rats, respectively. We identified the myocardial levels of phospho Akt and phosphoinositide 3-kinase, which are the upstream proteins of AMPK and MAPK activation and both were up-regulated in the vehicle-treated rats, whereas candesartan treatment significantly reversed these changes. We have also measured the myocardial levels of p-AMPKα, different isoforms of protein kinase C and MAPK signaling proteins. All of these protein levels were significantly elevated in the hearts of DCM rats whereas edaravone treatment significantly reversed these changes. In viewing these results, we can suggest that along with MAPK, AMPK signaling also plays a crucial role in the progression of EAM and it can be effectively blocked by the treatment with a novel antioxidant, edaravone.
authors.affiliation: Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, Niigata City 956-8603, Japan.
authors.forename: Somasundaram
authors.initials: S
authors.lastname: Arumugam
authors.forename: Rajarajan A
authors.initials: RA
authors.lastname: Thandavarayan
authors.forename: Punniyakoti T
authors.initials: PT
authors.lastname: Veeraveedu
authors.forename: Vijayasree V
authors.initials: VV
authors.lastname: Giridharan
authors.forename: Vivian
authors.initials: V
authors.lastname: Soetikno
authors.forename: Meilei
authors.initials: M
authors.lastname: Harima
authors.forename: Kenji
authors.initials: K
authors.lastname: Suzuki
authors.forename: Masaki
authors.initials: M
authors.lastname: Nagata
authors.forename: Ritsuo
authors.initials: R
authors.lastname: Tagaki
authors.forename: Makoto
authors.initials: M
authors.lastname: Kodama
authors.forename: Kenichi
authors.initials: K
authors.lastname: Watanabe
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D000818:Animals; D000983:Antipyrine / Q000031:analogs & derivatives* / Q000494:pharmacology; D001327:Autoimmune Diseases / Q000201:enzymology* / Q000473:pathology / Q000517:prevention & control; D004195:Disease Models, Animal; D018450:Disease Progression; D000077553:Edaravone; D016166:Free Radical Scavengers / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D009205:Myocarditis / Q000201:enzymology* / Q000473:pathology / Q000517:prevention & control; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D015398:Signal Transduction / Q000502:physiology
chemical_list: D016166:Free Radical Scavengers; D007527:Isoenzymes; D011494:Protein Kinases; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D000091162:AMP-Activated Protein Kinase Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D000077553:Edaravone; D000983:Antipyrine