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Glucose‐6‐Phosphate Dehydrogenase Regulate Metabolome‐Transcriptome Axis And Mitochondrial Malfunction In Diabetic Hearts: Implications In Pathogenesis Of Diabetic Cardiomyopathy And Mending Of Broken Hearts
Author(s) -
Dhagia Vidhi,
Joshi SachindraRaj,
Soldatos Vasiliki,
Rocic Petra,
Edwards John,
Gupte Sachin
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2018.32.1_supplement.903.12
Subject(s) - medicine , metabolome , endocrinology , diabetic cardiomyopathy , transcriptome , cardiac function curve , heart failure , cardiomyopathy , biology , metabolite , gene expression , biochemistry , gene
Rationale Cardiovascular performance and the progression of heart failure is worse in patients with metabolic syndrome or type II diabetes mellitus (T2DM) than in non‐diabetics. We hypothesized that increased glucose‐6‐phosphate dehydrogenase (G6PD) activity in the diabetic heart alters the transcriptome and metabolome profile and impairs mitochondrial function, leading to decreased myocardial function. Methods and Results We used hyperglycemic Goto‐Kakizaki (GK) rats fed a normal chow (NC) or a high fat diet (HFD) and JCR rats, a model of metabolic syndrome (MetS). Hemodynamics were evaluated through cardiac catheterization and metabolite profiling, and transcriptome analysis was used to detect molecular signatures underlying the disease condition. We found that cardiac contractility was decreased in GK‐NC and GK‐HFD rats, but left ventricular stiffness was increased only in GK‐HFD rats. In those hearts, G6PD activity was increased, and the G6PD activity correlated negatively with mitochondrial cytochrome c oxidase (COX) activity. Also increased was the expression of voltage‐dependent anion channel (VDAC), which was associated with increased cardiac cytosolic cytochrome c expression GK rats. In vitro experiments showed VDAC is regulated by miR‐31. Administration of epiandrosterone (30 mg/kg/day s.c.), a well‐known G6PD inhibitor, to JCR rats for 28 days increased fractional shortening, decreased LV stiffness, and attenuated fibrosis and neointimal growth in the coronary arteries as compared to vehicle treatment. This was accompanied by decreases in VDAC and increases in miR‐31. Metabolomic and transcriptomic analysis revealed that G6PD inhibition reversed MetS‐induced cardiac metabolic reprogramming and gene expression. Conclusion These findings suggest that increased G6PD activity suppresses mitochondrial respiratory chain enzymes, induces maladaptive overexpression of mitochondrial proteins through miR pathways, and evokes left ventricular stiffness in diabetic rats fed a HFD. Moreover, inhibition of G6PD reverses the fibrosis, metabolic reprogramming, and gene expression changes seen in hearts from diabetic and MetS animals. Support or Funding Information NIH RO1 HL 132574 (SAG) This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .