Premium
Up‐regulating Heme Oxygenase System Potentiates Pancreatic Repair by Enhancing Proteins of Regeneration
Author(s) -
Mishra Manish,
Ndisang Joseph Fomusi
Publication year - 2016
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.30.1_supplement.lb660
Subject(s) - streptozotocin , hemin , heme oxygenase , medicine , regeneration (biology) , diabetes mellitus , insulin , endocrinology , chemistry , microbiology and biotechnology , pharmacology , biology , heme , biochemistry , enzyme
Background Autoimmune‐mediated enhanced beta cell destruction and resultant insulin insufficiency poses a great health risk in type‐1 diabetes mellitus affected individuals. Our previous observations have shown that up‐regulation of the heme oxygenase (HO) by HO‐inducer hemin improved pancreatic lesion in streptozotocin‐induced diabetes, yet the hemin mediated pancreatic tissue repair mechanisms are still unclear. Accordingly, the aim of this study was to examine the effects of up‐regulating the HO system on proteins of regeneration during pancreatic repair in streptozotocin‐induced type‐1 diabetic animal model. Methods/Results Streptozotocin (STZ) was used to induce diabetes, while HO system was up‐regulated with hemin or inhibited with chromium mesoporphyrin. Histology/morphology, spectrophotometry, enzyme‐immunoassay (EIA), enzyme‐linked immunosorbent assay (ELISA) and Western‐immunoblotting were used to demonstrate pancreatic tissue injury and repair. Our data demonstrated that treatment with hemin to STZ‐induced diabetic animals effectively suppressed the pancreatic histopathological lesions (vacuolization, interstitial edema, mononuclear cell infiltration and fibrosis), while enhanced several proteins implicated in pancreatic repair/regeneration and beta cell growth and maturation including Oct3/4, Pax‐2, beta‐catenin, ISL‐1, glucose transporter‐2 (GLUT2), homeodomain protein NKK6.1. Interestingly, hemin treatment also increased the expression of stem cell markers such as cKit and Sca‐1, suggesting the involvement of stem cells and proteins of regeneration during pancreatic repair/regeneration in STZ diabetic animals. Moreover, the restoration of pancreatic morphology was accompanied by increased production of insulin and the potentiation of important proteins of insulin signaling pathway such as insulin‐receptor substrate (IRS‐1), IRS‐2, phosphatidylinositol‐3‐kinase (PI3K) and Glucose transporter‐4 (GLUT4) in skeletal muscles and the liver from STZ diabetic animals. Furthermore, hemin significantly reduced the inflammation and oxidative stress in the pancreas, skeletal muscles and liver, In contrast, these effects were nullified by the HO‐inhibitor, chromium mesoporphyrin. Conclusion Taken together, our findings demonstrate that upregulating the HO‐system with hemin is a useful strategy to potentiate proteins of regeneration such as Oct3/4, Pax‐2, beta‐catenin, ISL‐1 , GLUT2 and NKK6.1 during the restoration of pancreatic morphology in streptozotocin‐induced diabetic animals. Importantly, the restoration of pancreatic morphology was accompanied by improved insulin production and the potentiation of proteins implicated in insulin signaling and glucose metabolism. Thus, HO‐inducers may open a new horizon in the search for remedies of type‐1 diabetes. Support or Funding Information Heart & Stroke Foundation of Saskatchewan, Canada