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Phospholipase A2-modified low density lipoprotein induces mitochondrial uncoupling and lowers reactive oxygen species

Dmitry Namgaladze1, Stefan Preiss, Stefan Dröse

  • 1Goethe-University, Faculty of Medicine, Institute of Biochemistry I/ZAFES, Theodor-Stern-Kai 7, Frankfurt, Germany.

Atherosclerosis
|August 4, 2009
PubMed

Insights

Secretory phospholipase A(2)-modified low-density lipoprotein (PLA-LDL) causes mitochondrial uncoupling in monocytes, reducing reactive oxygen species. This may enhance monocyte survival, potentially promoting atherosclerosis.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Cardiovascular Research

Background:

  • Secretory phospholipase A(2) (PLA(2)) modifies low-density lipoprotein (LDL), creating PLA-LDL.
  • PLA-LDL is known to protect monocytes from oxidative stress.
  • The direct impact of PLA-LDL on mitochondrial function and reactive oxygen species (ROS) generation requires elucidation.

Purpose of the Study:

  • To investigate the direct effects of PLA-LDL on mitochondrial membrane potential and ROS generation in monocytes.
  • To determine the role of non-esterified fatty acids and uncoupling protein 2 (UCP2) in PLA-LDL-induced mitochondrial changes.
  • To assess the impact of PLA-LDL-induced mitochondrial uncoupling on monocyte survival under oxidative stress.

Main Methods:

  • Mitochondrial membrane potential assessed using flow cytometry (5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolylcarbocyanine iodide) and respirometry.
  • ROS generation measured by flow cytometry (2',7'-dichlorofluorescin oxidation).
  • Cell death evaluated using Annexin V/propidium iodide staining; UCP2 knockdown performed.

Main Results:

  • PLA-LDL induced mitochondrial uncoupling in both monocyte/macrophage cell lines and primary human monocytes.
  • Non-esterified fatty acids associated with PLA-LDL were identified as the cause of uncoupling.
  • This uncoupling attenuated ROS production triggered by various agents, including hydrogen peroxide and oxidized LDL.
  • UCP2 knockdown did not influence PLA-LDL-induced uncoupling or ROS reduction.
  • Chemical uncouplers enhanced monocyte survival against hydrogen peroxide-induced cell death.

Conclusions:

  • PLA-LDL-induced mitochondrial uncoupling effectively reduces ROS generation in monocytes.
  • This mechanism may contribute to enhanced monocyte survival within atherosclerotic plaques.
  • The findings suggest PLA-LDL plays a pro-atherogenic role by modulating monocyte bioenergetics and survival.

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