Myeloperoxidase-oxidized high density lipoprotein impairs atherosclerotic plaque stability by inhibiting smooth muscle cell migration

Abstract

BackgroundHigh density lipoprotein (HDL) has been proved to be a protective factor for coronary heart disease. Notably, HDL in atherosclerotic plaques can be nitrated (NO2-oxHDL) and chlorinated (Cl-oxHDL) by myeloperoxidase (MPO), likely compromising its cardiovascular protective effects.MethodHere we determined the effects of NO2-oxHDL and Cl-oxHDL on SMC migration using wound healing and transwell assays, proliferation using MTT and BrdU assays, and apoptosis using Annexin-V assay in vitro, as well as on atherosclerotic plaque stability in vivo using a coratid artery collar implantation mice model.ResultsOur results showed that native HDL promoted SMC proliferation and migration, whereas NO2-oxHDL and Cl-oxHDL inhibited SMC migration and reduced capacity of stimulating SMC proliferation as well as migration, respectively. OxHDL had no significant influence on SMC apoptosis. In addition, we found that ERK1/2-phosphorylation was significantly lower when SMCs were incubated with NO2-oxHDL and Cl-oxHDL. Furthermore, transwell experiments showed that differences between native HDL, NO2-oxHDL and Cl-oxHDL was abolished after PD98059 (MAPK kinase inhibitor) treatment. In aortic SMCs from scavenger receptor BI (SR-BI) deficient mice, differences between migration of native HDL, NO2-oxHDL and Cl-oxHDL treated SMCs vanished, indicating SR-BI’s possible role in HDL-associated SMC migration. Importantly, NO2-oxHDL and Cl-oxHDL induced neointima formation and reduced SMC positive staining cells in atherosclerotic plaque, resulting in elevated vulnerable index of atherosclerotic plaque.ConclusionThese findings implicate MPO-catalyzed oxidization of HDL may contribute to atherosclerotic plaque instability by inhibiting SMC proliferation and migration through MAPK-ERK pathway which was dependent on SR-BI.Electronic supplementary materialThe online version of this article (doi:10.1186/s12944-016-0388-z) contains supplementary material, which is available to authorized users.

Biological Consequences of Dysfunctional HDL

“…The latter observation is in line with the ability of chlorinated and nitrated HDL to inhibit SMC migration and exhibit a reduced ability to stimulate SMC proliferation, without significant effects on SMC apoptosis [153]. Furthermore, in experimental models of carotid stenosis, the injection of chlorinated or nitrated HDL resulted in increased neointima/media ratio and reduced SMC positive staining cells in the fibrous cap compared to native HDL-treated mice, thus suggesting that MPO-HDL might increase the vulnerability index of the plaque [153].…”

The Role of Myeloperoxidase in Biomolecule Modification, Chronic Inflammation, and Disease

“…In this case, in contrast to observations with native apoA1, apoA1 oxidized by MPO failed to decrease macrophage number in the lesions or promote a noninflammatory macrophage phenotype (101). Finally, HOCl-induced modification of HDL inhibits the migration and proliferation of VSMC (311). This suggests that MPO-dependent HDL modifications can potentially promote inflammation, lesion development, and plaque instability in atherosclerosis.…”

Myeloperoxidase level and inflammatory markers and lipid and lipoprotein parameters in stable coronary artery disease

“…Khine HW et al [ 5 ] showed that increased MPO indexed to HDL particle concentration (MPO/HDLp) is associated with increased risk of incident CVD (cardiovascular disease) events in a population initially free of CVD. MPO may contribute to atherosclerotic plaque instability [ 22 ].…”