Expression of Endothelial Lipase Correlates with the Size of Neointima in a Murine Model of Vascular Remodeling

Abstract

Aim: Endothelial lipase (EL) regulates plasma high-density lipoprotein-cholesterol (HDL-C) levels by promoting HDL catabolism. However, it remains unknown whether the inhibition of EL has beneficial effects on the genesis of vascular diseases. Here, we investigated the role of EL on vascular remodeling in mice. Methods: Vascular remodeling was developed by ligation of the left common carotid artery and neointimal lesions were histologically compared between EL-knockout (ELKO), EL-transgenic (ELTg), and wild-type (WT) mice. HDL was isolated from these mice, and effects of the HDL on cell growth and Erk activation were evaluated in vitro using cultured vascular smooth muscle cells. Results: Plasma HDL-C levels were 62% higher in ELKO and 13% lower in ELTg than in WT mice, after the carotid ligation. The size of neointimal lesion was significantly larger in ELTg and smaller in ELKO than in WT mice. Vascular expression of adhesion molecules was lower in ELKO and higher in ELTg compared with WT mice. Moreover, oxidative stress was attenuated in ELKO mice. HDL isolated from ELKO, ELTg, and WT mice inhibited expression of intercellular adhesion molecule-1, angiotensin Ⅱ-induced activation of Erk, and growth of cultured vascular smooth muscle cells, whereas EL expression itself did not affect cell migration or growth. Conclusion: EL expression modulates vascular remodeling as well as plasma HDL-C levels. EL inactivation may increase HDL particles that can inhibit smooth muscle cell growth and migration.

Oxidized High-Density Lipoprotein Induces the Proliferation and Migration of Vascular Smooth Muscle Cells by Promoting the Production of ROS

“…VSMC proliferation and migration induced by Ang-Ⅱ; however, decreasing the HDL concentration in EL transgenic mice enhances proliferation and migration in cultured VSMCs 14) . Our results are also consistent with the conclusion that N-HDL does not promote VSMC proliferation or migration (Fig.…”

“…HDL inhibits VSMC migration via the sphingosine-1-phosphate (S1P)-2 receptor induced by PDGF 13) . Sun et al also showed that endothelial lipase (EL) inactivation increases the amount of plasma HDL particles that can inhibit VSMC growth and migration induced by Ang-Ⅱ; however, EL overexpression decreases the HDL concentration, which increases the proliferation and migration of cultured VSMCs 14) . Meanwhile, increasing evidence has shown that HDL can lose its protective properties and even develop proinflammatory and proatherogenic phenotypes in the setting of systemic inflammation, including conditions such as atherosclerosis, diabetes mellitus and metabolic syndrome [15][16][17] .…”

Interleukin 6 Stimulates Endothelial Binding and Transport of High-Density Lipoprotein Through Induction of Endothelial Lipase

“…However, both gene targeting in mice and Mendelian randomization experiments in humans produced controversial results on the effect of EL on atherosclerosis and cardiovascular risk, respectively. [31][32][33][34][35] In addition, the lipolytic products generated by EL in HDL were previously shown to exert both putatively pro-and antiatherogenic activities. [36][37][38][39] Indeed, Hara et al 37 reported that EL deletion resulted in increased HDL and anti-inflammatory function in the plasma compartment; Ahmed et al 39 showed that HDL lipolysis by EL mediates repression of vascular cell adhesion molecule 1 expression.…”

“…However, both gene targeting in mice and Mendelian randomization experiments in humans produced controversial results on the effect of EL on atherosclerosis and cardiovascular risk, respectively. [31][32][33][34][35] In addition, the lipolytic products generated by EL in HDL were previously shown to exert both putatively pro-and antiatherogenic activities.…”

The apolipoprotein A‐I mimetic peptide, D‐4F, restrains neointimal formation through heme oxygenase‐1 up‐regulation

“…In addition, HDL strikingly reduces the proliferation of VSMCs and prevents the pathogenesis of neointimal hyperplasia 12. Decreased HDL levels in endothelial lipase (EL)‐transgenic mice increase oxidative stress and promote neointimal formation in carotid arteries 13.…”