title: The hyperglycemia stimulated myocardial endoplasmic reticulum (ER) stress contributes to diabetic cardiomyopathy in the transgenic non-obese type 2 diabetic rats: a differential role of unfolded protein response (UPR) signaling proteins.
abstract: It has been well demonstrated that excessive blood glucose level could be detrimental to the myocardial function through the variety of mechanisms, of which endoplasmic reticulum stress (ERS) could play an unprecedented role through the activation of unfolded protein response (UPR). Recently, reports are coming out with the evidences that UPR signaling proteins are regulated differentially depend on the experimental conditions and cell types. In addition, ERS has been proposed to be closely associated with the regulation of lipogenesis. Therefore, in this study we tried to find out the expressions of myocardial UPR signaling proteins as well as proteins involved in lipid and glucose metabolism in non-obese type 2 diabetic mellitus (DM) condition using Spontaneous Diabetic Torii (SDT) rat. We have found the significant up-regulation of oxidative, nitrosative and ERS marker proteins in the myocardium of the SDT rats, in comparison to its normal (Sprague-Dawley - SD) rats. In addition, the sub-arm of UPR signaling proteins, such as p-PERK, p-eIF2α, ATF6, CHOP/GADD153, TRAF2, apoptotic signaling proteins, such as BAD, cytochrome C, cleaved caspase-7 and -12, were significantly up-regulated in the SDT rats, in comparison to the SD rats. Interestingly, there were no significant changes in the phosphorylation of IRE-1α, and XBP-1 protein expression. In addition, the proteins involved in lipid and glucose metabolisms, such as PPARα, PPARγ, CPT1, PGC-1α except GLUT4, and the proteins involved in insulin signaling, such as p-Akt and p-PI3K were shown significant attenuation in its expressions in the SDT rats, when compared with the SD rats. Taken together, it is suggested that the activation of PERK and ATF6 pathway are the major determinant rather than the IRE-1α-XBP1 pathway for the ERS-mediated metabolic dysfunction, which might eventually leads to diabetic cardiomyopathy in non-obese type 2 DM.
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: Arun Prasath
authors.initials: AP
authors.lastname: Lakshmanan
authors.forename: Meilei
authors.initials: M
authors.lastname: Harima
authors.forename: Kenji
authors.initials: K
authors.lastname: Suzuki
authors.forename: Vivian
authors.initials: V
authors.lastname: Soetikno
authors.forename: Masaki
authors.initials: M
authors.lastname: Nagata
authors.forename: Takashi
authors.initials: T
authors.lastname: Nakamura
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Takahashi
authors.forename: Hirohito
authors.initials: H
authors.lastname: Sone
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kawachi
authors.forename: Kenichi
authors.initials: K
authors.lastname: Watanabe
mesh_terms: D051702:Activating Transcription Factor 6 / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000378:metabolism*; D058065:Diabetic Cardiomyopathies / Q000378:metabolism* / Q000473:pathology; D059865:Endoplasmic Reticulum Stress; D006943:Hyperglycemia / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D008297:Male; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D056811:Unfolded Protein Response
chemical_list: D051702:Activating Transcription Factor 6; C497113:Atf6 protein, rat; D047908:Intracellular Signaling Peptides and Proteins; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt