Proteomic analysis of hearts from Akita mice suggests that increases in soluble epoxide hydrolase and antioxidative programming are key changes in early stages of diabetic cardiomyopathy

Shannamar Dewey, Xianyin Lai, Frank A. Witzmann, Mandeep Sohal, Aldrin V Gomes

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Cardiovascular disease is the leading cause of diabetic morbidity with more than 10% of type 1 diabetes mellitus (T1DM) patients dying before they are 40 years old. This study utilized Akita mice, a murine model with T1DM progression analogous to that of humans. Diabetic cardiomyopathy in Akita mice presents as cardiac atrophy and diastolic impairment at 3 months of age, but we observed cardiac atrophy in hearts from recently diabetic mice (5 weeks old). Hearts from 5 week old mice were analyzed with a rigorous label-free quantitative proteomic approach to identify proteins that may play a critical role in the early pathophysiology of diabetic cardiomyopathy. Eleven proteins were differentially expressed in diabetic hearts: products of GANC, PLEKHN1, COL1A1, GSTK1, ATP1A3, RAP1A, ACADS, EEF1A1, HRC, EPHX2, and PKP2 (gene names). These proteins are active in cellular defense, metabolism, insulin signaling, and calcium handling. Further analysis of Akita hearts using biochemical assays showed that the cellular defenses against oxidative stress were increased, including antioxidant capacity (2-3-fold) and glutathione levels (20%). Immunoblots of five and twelve week old Akita heart homogenates showed 30% and 145% increases in expression of soluble epoxide hydrolase (sEH (gene name EPHX2)), respectively, and an approximate 100% increase in sEH was seen in gastrocnemius tissue of 12 week old Akita mice. In contrast, 12 week old Akita livers showed no change in sEH expression. Our results suggest that increases in sEH and antioxidative programming are key factors in the development of type 1 diabetic cardiomyopathy in Akita mice and reveal several other proteins whose expression may be important in this complex pathophysiology.

Original languageEnglish (US)
Pages (from-to)3920-3933
Number of pages14
JournalJournal of Proteome Research
Volume12
Issue number9
DOIs
StatePublished - Sep 6 2013

Fingerprint

Diabetic Cardiomyopathies
Epoxide Hydrolases
Proteomics
Medical problems
Type 1 Diabetes Mellitus
Proteins
Genes
Atrophy
Names
Oxidative stress
Calcium Signaling
Metabolism
Liver
Glutathione
Labels
Assays
Antioxidants
Insulin
Tissue
Calcium

Keywords

  • diabetes mellitus (DM)
  • diabetic cardiomyopathy (DC)
  • heart
  • mass spectrometry (MS)
  • murine

ASJC Scopus subject areas

  • Biochemistry
  • Chemistry(all)

Cite this

Proteomic analysis of hearts from Akita mice suggests that increases in soluble epoxide hydrolase and antioxidative programming are key changes in early stages of diabetic cardiomyopathy. / Dewey, Shannamar; Lai, Xianyin; Witzmann, Frank A.; Sohal, Mandeep; Gomes, Aldrin V.

In: Journal of Proteome Research, Vol. 12, No. 9, 06.09.2013, p. 3920-3933.

Research output: Contribution to journalArticle

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abstract = "Cardiovascular disease is the leading cause of diabetic morbidity with more than 10{\%} of type 1 diabetes mellitus (T1DM) patients dying before they are 40 years old. This study utilized Akita mice, a murine model with T1DM progression analogous to that of humans. Diabetic cardiomyopathy in Akita mice presents as cardiac atrophy and diastolic impairment at 3 months of age, but we observed cardiac atrophy in hearts from recently diabetic mice (5 weeks old). Hearts from 5 week old mice were analyzed with a rigorous label-free quantitative proteomic approach to identify proteins that may play a critical role in the early pathophysiology of diabetic cardiomyopathy. Eleven proteins were differentially expressed in diabetic hearts: products of GANC, PLEKHN1, COL1A1, GSTK1, ATP1A3, RAP1A, ACADS, EEF1A1, HRC, EPHX2, and PKP2 (gene names). These proteins are active in cellular defense, metabolism, insulin signaling, and calcium handling. Further analysis of Akita hearts using biochemical assays showed that the cellular defenses against oxidative stress were increased, including antioxidant capacity (2-3-fold) and glutathione levels (20{\%}). Immunoblots of five and twelve week old Akita heart homogenates showed 30{\%} and 145{\%} increases in expression of soluble epoxide hydrolase (sEH (gene name EPHX2)), respectively, and an approximate 100{\%} increase in sEH was seen in gastrocnemius tissue of 12 week old Akita mice. In contrast, 12 week old Akita livers showed no change in sEH expression. Our results suggest that increases in sEH and antioxidative programming are key factors in the development of type 1 diabetic cardiomyopathy in Akita mice and reveal several other proteins whose expression may be important in this complex pathophysiology.",
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