LR-90 prevents methylglyoxal-induced oxidative stress and apoptosis in human endothelial cells.

Abstract

Methylglyoxal (MGO) is a highly reactive dicarbonyl compound known to induce cellular injury and cytoxicity, including apoptosis in vascular cells. Vascular endothelial cell apoptosis has been implicated in the pathophysiology and progression of atherosclerosis. We investigated whether the advanced glycation end-product inhibitor LR-90 could prevent MGO-induced apoptosis in human umbilical vascular endothelial cells (HUVECs). HUVECs were pre-treated with LR-90 and then stimulated with MGO. Cell morphology, cytotoxicity and apoptosis were evaluated by light microscopy, MTT assay, and Annexin V-FITC and propidium iodide double staining, respectively. Levels of Bax, Bcl-2, cytochrome c, mitogen-activated protein kinases (MAPKs) and caspase activities were assessed by Western blotting. Reactive oxygen species (ROS) generation and mitochondrial membrane potential (MMP) were measured with fluorescent probes. LR-90 dose-dependently prevented MGO-associated HUVEC cytotoxicity and apoptotic biochemical changes such as loss of MMP, increased Bax/Bcl-2 protein ratio, mitochondrial cytochrome c release and activation of caspase-3 and 9. Additionally, LR-90 blocked intracellular ROS formation and MAPK (p44/p42, p38, JNK) activation, though the latter seem to be not directly involved in MGO-induced HUVEC apoptosis. LR-90 prevents MGO-induced HUVEC apoptosis by inhibiting ROS and associated mitochondrial-dependent apoptotic signaling cascades, suggesting that LR-90 possess cytoprotective ability which could be beneficial in prevention of diabetic related-atherosclerosis.

• Authors: James L Figarola, Jyotsana Singhal, Samuel Rahbar, Sanjay Awasthi, Sharad S Singhal
• Journal: Apoptosis : an international journal on programmed cell death (Apoptosis) Vol. 19 Issue 5 Pg. 776-88 (May 2014) ISSN: 1573-675X [Electronic] Netherlands
• PMID: 24615331 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antioxidants
• Butyrates
• LR-90
• Reactive Oxygen Species
• Pyruvaldehyde
• Cytochromes c
• Mitogen-Activated Protein Kinases
• Caspases

Topics

• Antioxidants (pharmacology)
• Apoptosis (drug effects)
• Butyrates (pharmacology)
• Caspases (metabolism)
• Cytochromes c (metabolism)
• Enzyme Activation
• Human Umbilical Vein Endothelial Cells (cytology, drug effects, metabolism)
• Humans
• Membrane Potential, Mitochondrial (drug effects)
• Mitochondria (drug effects, metabolism)
• Mitochondrial Membranes (drug effects, metabolism)
• Mitogen-Activated Protein Kinases (metabolism)
• Oxidative Stress (drug effects)
• Pyruvaldehyde (metabolism, toxicity)
• Reactive Oxygen Species (metabolism)
• Signal Transduction (drug effects)