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

Arun Lakshmanan, Meilei Harima, Kenji Suzuki, Vivian Soetikno, Masaki Nagata, Takashi Nakamura, Toshihiro Takahashi, Hirohito Sone, Hiroshi Kawachi, Kenichi Watanabe

Research output: Contribution to journalArticle

49 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)438-447
Number of pages10
JournalInternational Journal of Biochemistry and Cell Biology
Volume45
Issue number2
DOIs
Publication statusPublished - 1 Feb 2013
Externally publishedYes

Fingerprint

Diabetic Cardiomyopathies
Unfolded Protein Response
Endoplasmic Reticulum Stress
Hyperglycemia
Rats
Peroxisome Proliferator-Activated Receptors
Proteins
Lipid Metabolism
TNF Receptor-Associated Factor 2
Caspase 12
Glucose Transporter Type 4
Caspase 7
Glucose
Lipogenesis
Cytochromes
Heat-Shock Proteins
Phosphatidylinositol 3-Kinases
Metabolism
Sprague Dawley Rats
Blood Glucose

Keywords

  • ATF6
  • ERS
  • IRE-1α-XBP1 pathway
  • PERK-CHOP/GADD153 axis
  • Spontaneous Diabetic Torii

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology

Cite this

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. / Lakshmanan, Arun; Harima, Meilei; Suzuki, Kenji; Soetikno, Vivian; Nagata, Masaki; Nakamura, Takashi; Takahashi, Toshihiro; Sone, Hirohito; Kawachi, Hiroshi; Watanabe, Kenichi.

In: International Journal of Biochemistry and Cell Biology, Vol. 45, No. 2, 01.02.2013, p. 438-447.

Research output: Contribution to journalArticle

Lakshmanan, Arun ; Harima, Meilei ; Suzuki, Kenji ; Soetikno, Vivian ; Nagata, Masaki ; Nakamura, Takashi ; Takahashi, Toshihiro ; Sone, Hirohito ; Kawachi, Hiroshi ; Watanabe, Kenichi. / 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. In: International Journal of Biochemistry and Cell Biology. 2013 ; Vol. 45, No. 2. pp. 438-447.
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