Low-density lipoprotein modified by myeloperoxidase oxidants induces endothelial dysfunction

Area of Science:

• Biochemistry
• Cardiovascular Biology
• Oxidative Stress

Background:

• Low-density lipoprotein (LDL) modified by myeloperoxidase (MPO) is found in atherosclerotic lesions.
• MPO uses thiocyanate (SCN-) to produce hypothiocyanous acid (HOSCN), which modifies LDL differently than hypochlorous acid (HOCl).
• Elevated plasma SCN- has paradoxical roles in atherosclerosis, potentially promoting or preventing it.

Purpose of the Study:

• To investigate the role of HOSCN-modified LDL in endothelial dysfunction.
• To compare the effects of HOSCN-modified LDL with HOCl-modified LDL on endothelial function.
• To elucidate the mechanisms by which MPO-modified LDL induces endothelial dysfunction.

Main Methods:

• Ex vivo studies using rat aortic ring segments to assess endothelium-mediated vasorelaxation.
• In vitro experiments with human coronary artery endothelial cells.
• Analysis of nitric oxide (NO•) production, endothelial nitric oxide synthase (eNOS) activity, expression, phosphorylation, and cellular localization.

Main Results:

• Both HOSCN- and HOCl-modified LDL significantly inhibit endothelium-mediated vasorelaxation.
• HOSCN-modified LDL decreases NO• production and eNOS activity in endothelial cells, similar to HOCl-modified LDL.
• These effects are attributed to eNOS uncoupling, not changes in expression, phosphorylation, or localization.

Conclusions:

• MPO-mediated modification of LDL by HOSCN contributes to endothelial dysfunction.
• HOSCN-modified LDL impairs vasorelaxation and reduces NO• bioavailability through eNOS uncoupling.
• Findings have implications for understanding atherosclerosis, the therapeutic use of SCN-, and cardiovascular risks in smokers.