Foam cell formation reduces cellular vitamin E and increases the susceptibility of human macrophages to lysis by oxidized LDL

Human heregulins, neuregulin-1 type I polypeptides known to activate proliferation, differentiation, and survival of glial cells, neurons, and myocytes, were recently found to be expressed in macrophage foam cells within human coronary atherosclerotic lesions. Macrophage foam cell formation, characterized by cholesterol ester (CE) accumulation, is modulated by scavenger receptor class A (SR-A), acyl-CoA:cholesterol acyltransferase-1 (ACAT1), and ATP-binding cassette transporter A1 (ABCA1). The present study clarified the functional roles of heregulins in macrophage foam cell formation and atherosclerosis. Plasma heregulin-beta1 levels were significantly decreased in 31 patients with acute coronary syndrome (ACS) and 33 patients with stable angina pectoris as compared with 34 mild hypertensive patients and 40 healthy volunteers (1.3+/−0.3, 2.0+/−0.4 versus 7.6+/−1.4, 8.2+/−1.2 ng/mL; at least P < 0.01). Immunoreactive heregulins and these receptor c-erbB3 were detectable within human coronary atherothrombosis obtained from ACS patients. In primary cultured human monocyte-macrophages, the expression of endogenous heregulins, heregulin-beta1, and c-erbB3 increased during monocytic differentiation into macrophages. In human macrophages differentiated by 7-day culture, exogenous heregulin-beta1, but not heregulin-alpha, significantly reduced acetylated low-density lipoprotein (acLDL)-induced CE accumulation by reducing SR-A and ACAT1 expression and by increasing ABCA1 expression at both mRNA and protein levels. Heregulin-beta1 significantly decreased endocytic uptake of [ 125 I]acLDL and increased cholesterol efflux by apolipoprotein A1 from human macrophages. Chronic infusion of heregulin-beta1 by osmotic mini-pumps into apolipoprotein E-deficient mice significantly suppressed the progression of macrophage-driven atherosclerotic lesions by 64%. Our study provides the first evidence that heregulin-beta1 may participate in anti-atherogenesis by suppressing macrophage foam cell formation via SR-A and ACAT1 down-regulation and ABCA1 up-regulation.

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Anti-Atherosclerotic Activity of (3R)-5-Hydroxymellein from an Endophytic Fungus Neofusicoccum parvum JS-0968 Derived from Vitex rotundifolia through the Inhibition of Lipoproteins Oxidation and Foam Cell Formation

Biomolecules ◽

10.3390/biom10050715 ◽

2020 ◽

Vol 10 (5) ◽

pp. 715

Author(s):

Jae-Yong Kim ◽

Soonok Kim ◽

Sang Hee Shim

Keyword(s):

Conformational Changes ◽

Endophytic Fungus ◽

Foam Cell ◽

Oxidized Ldl ◽

Cell Formation ◽

Density Lipoprotein ◽

Ldl Oxidation ◽

Foam Cell Formation ◽

Macrophage Foam Cell ◽

Neofusicoccum Parvum

An endophytic fungus, Neofusicoccum parvum JS-0968, was isolated from a plant, Vitex rotundifolia. The chemical investigation of its cultures led to the isolation of a secondary metabolite, (3R)-5-hydroxymellein. It has been reported to have antifungal, antibacterial, and antioxidant activity, but there have been no previous reports on the effects of (3R)-5-hydroxymellein on atherosclerosis. The oxidation of lipoproteins and foam cell formation have been known to be significant in the development of atherosclerosis. Therefore, we investigated the inhibitory effects of (3R)-5-hydroxymellein on atherosclerosis through low-density lipoprotein (LDL) and high-density lipoprotein (HDL) oxidation and macrophage foam cell formation. LDL and HDL oxidation were determined by measuring the production of conjugated dienes and malondialdehyde, the amount of hyperchromicity and carbonyl content, conformational changes, and anti-LDL oxidation. In addition, the inhibition of foam cell formation was measured by Oil red O staining. As a result, (3R)-5-hydroxymellein suppressed the oxidation of LDL and HDL through the inhibition of lipid peroxidation, the decrease of negative charges, the reduction of hyperchromicity and carbonyl contents, and the prevention of apolipoprotein A-I (ApoA-I) aggregation and apoB-100 fragmentation. Furthermore, (3R)-5-hydroxymellein significantly reduced foam cell formation induced by oxidized LDL (oxLDL). Taken together, our data show that (3R)-5-hydroxymellein could be a potential preventive agent for atherosclerosis via obvious anti-LDL and HDL oxidation and the inhibition of foam cell formation.

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