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Oxidative and endoplasmic reticulum stresses mediate apoptosis induced by modified LDL in human retinal Müller cells

Mingyuan Wu1, Shihe Yang, Michael H Elliott

  • 1Harold Hamm Diabetes Center, Oklahoma City, Oklahoma, USA.

Investigative Ophthalmology & Visual Science
|June 9, 2012
PubMed
Abstract

Insights

Modified LDL induces apoptosis in retinal Müller cells by increasing oxidative and ER stress. These findings highlight modified LDL as a key factor in diabetic retinopathy progression.

Area of Science:

  • Ophthalmology
  • Cell Biology
  • Diabetic Retinopathy Research

Background:

  • Diabetic retinopathy (DR) is associated with pericyte loss, linked to extravasated, modified low-density lipoprotein (LDL).
  • The specific mechanisms by which modified LDL affects retinal cells in DR remain under investigation.

Purpose of the Study:

  • To investigate whether modified LDL induces apoptosis in human retinal Müller cells.
  • To elucidate the roles of oxidative stress and endoplasmic reticulum (ER) stress in this process.

Main Methods:

  • Cultured human retinal Müller cells (MIO-M1) were treated with highly oxidized glycated LDL (HOG-LDL) or native LDL (N-LDL).
  • Cells were also treated with oxidative/ER stress inducers (7-ketocholesterol, 4-hydroxynonenal) and with antioxidants/ER stress blockers (N-acetyl-cysteine, 4-phenylbutyrate).
  • Apoptosis, oxidative stress, and ER stress markers were assessed using cell viability assays, TUNEL staining, and Western blot.

Main Results:

  • HOG-LDL significantly induced apoptosis, characterized by decreased cell viability and increased apoptotic markers (cleaved PARP, cleaved caspase-3, BAX).
  • HOG-LDL also elevated markers of oxidative stress (NOX4, catalase, superoxide dismutase 2) and ER stress (phospho-eIF2α, KDEL, ATF6, CHOP).
  • N-acetyl-cysteine and 4-phenylbutyrate partially protected against HOG-LDL-induced apoptosis and ER stress, while 7-ketocholesterol and 4-hydroxynonenal mimicked HOG-LDL effects.

Conclusions:

  • Extravasated, modified lipoproteins, particularly oxidized LDL, contribute to Müller cell apoptosis in diabetic retinopathy.
  • Oxidative and ER stresses are key pathways mediating HOG-LDL-induced Müller cell death.
  • Modified LDL represents a significant retinal insult in diabetic retinopathy, beyond hyperglycemia.

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