Heme oxygenase‑1 alleviates advanced glycation end product‑induced oxidative stress, inflammatory response and biological behavioral disorders in rat dermal fibroblasts

Abstract

Advanced glycation end products (AGEs) are involved in delaying the wound healing of diabetic foot ulcers. The present study investigated the effects of heme oxygenase-1 (HO-1) on oxidative stress, inflammatory insult and biological behaviors in rat dermal fibroblasts in the presence of AGEs. Rat dermal fibroblasts were cultured in the presence of AGEs (100 µg/ml), glucose (1.0 g/l or 4.5 g/l), hemin (5 µM) and chromium mesoporphyrin (CrMP; 20 µM). A bilirubin kit, reverse transcription-quantitative PCR and western blotting were used to measure the activity and mRNA and protein levels of HO-1, respectively. ELISA kits were used to measure the levels of reactive oxygen species (ROS), malondialdehyde (MDA), 8-hydroxydeoxyguanosine (8-OHdG), TNF-α, IL-6, IL-1β and the viability and collagen (hydroxyproline) secretion of fibroblasts. Cell proliferation and apoptosis were measured via flow cytometry. The scratch test was performed to evaluate cell migration. The results revealed that AGEs resulted in oxidative stress, inflammatory response and biological behavioral disorders in fibroblasts, while worsened functional disorders were caused by the combination of AGEs and high-glucose treatment. Hemin treatment induced sustained high HO-1 expression, decreased the levels of ROS, MDA, 8-OHdG, TNF-α, IL-6, IL-1β and cell apoptosis, and increased cellular collagen synthesis, viability, proliferation and migration, whereas CrMP abolished the effects of hemin. It was observed that high HO-1 expression reversed the AGE-induced oxidative stress, inflammatory response and biological behavioral disorders in fibroblasts, but fibroblast function did not return to that observed under normal glucose levels. In conclusion, it was demonstrated that hemin treatment induced high HO-1 expression. HO-1 reduced the AGE-induced functional disorders in fibroblasts and may accelerate the healing of diabetic wounds by improving fibroblast biological behaviors and reducing the oxidative stress and inflammatory response.

Deciphering The Emerging Role of Programmed Cell Death in Diabetic Wound Healing

“…Besides, advanced glycation end products (AGEs) could induce oxidative stress and inflammatory responses in fibroblasts, which were closely related to fibroblast apoptosis 27 . Lao et al found that tissue inhibitor of metalloproteinases-1 (TIMP-1) levels were significantly reduced in AGEs-treated fibroblasts, and TIMP-1 could effectively reduce apoptosis 28 .…”

The role of programmed cell death in diabetic foot ulcers

“…Irisin, a cleavage product of the type I membrane protein encoded by FNDC5, activates the Notch pathway and inhibits apoptosis in HUVECs and increases the expression of Bcl‐2 and VEGFA thereby accelerating wound healing 54 . Haeme oxygenase‐1 (HO‐1) is an antioxidant, anti‐inflammatory and cytoprotective enzyme that inhibits NHDF apoptosis and accelerates wound healing in diabetes 55 . Tissue inhibitor of metalloproteinase‐1 (TIMP‐1), a glycoprotein expressed in various tissues, promotes cell growth and inhibits apoptosis.…”

“… 54 Haeme oxygenase‐1 (HO‐1) is an antioxidant, anti‐inflammatory and cytoprotective enzyme that inhibits NHDF apoptosis and accelerates wound healing in diabetes. 55 Tissue inhibitor of metalloproteinase‐1 (TIMP‐1), a glycoprotein expressed in various tissues, promotes cell growth and inhibits apoptosis. The levels of TIMP‐I are downregulated in diabetic foot skin tissue and AGE‐treated fibroblast culture supernatants, and increasing TIMP‐I expression can inhibit fibroblast apoptosis and accelerate wound healing in diabetic rats.…”

Rutin Promotes Wound Healing by Inhibiting Oxidative Stress and Inflammation in Metformin-Controlled Diabetes in Rats

“…This overproduction of cytokines leads to increased tissue damage and delayed diabetic wound healing. Also, prolonged hyperglycemia increases reactive oxygen species (ROS) production and oxidative injury. , Therefore, the primary reason for a longer healing time in diabetic wound patients is prolonged inflammation, and attenuation of inflammation and oxidative stress is essential to expedite the healing of diabetic wounds.…”