Preventive effects of heregulin-beta1 on macrophage foam cell formation and atherosclerosis.
BACKGROUND
Human heregulins, neuregulin-1 type I polypeptides that activate proliferation, differentiation, and survival of glial cells, neurons, and myocytes, are expressed in macrophage foam cells within human coronary atherosclerotic lesions. Macrophage foam cell formation, characterized by cholesterol ester accumulation, is modulated by scavenger receptor class A (SR-A), acyl-coenzyme A:cholesterol acyltransferase (ACAT)1, and ATP-binding cassette transporter (ABC)A1.


OBJECTIVE
The present study clarified the roles of heregulins in macrophage foam cell formation and atherosclerosis.


RESULTS
Plasma heregulin-beta(1) levels were significantly decreased in 31 patients with acute coronary syndrome and 33 patients with effort angina pectoris compared with 34 patients with mild hypertension and 40 healthy volunteers (1.3+/-0.3, 2.0+/-0.4 versus 7.6+/-1.4, 8.2+/-1.2 ng/mL; P<0.01). Among all patients with acute coronary syndrome and effort angina pectoris, plasma heregulin-beta(1) levels were further decreased in accordance with the severity of coronary artery lesions. Expression of heregulin-beta(1) was observed at trace levels in intracoronary atherothrombosis obtained by aspiration thrombectomy from acute coronary syndrome patients. Heregulin-beta(1), but not heregulin-alpha, significantly reduced acetylated low-density lipoprotein-induced cholesterol ester accumulation in primary cultured human monocyte-derived macrophages by reducing SR-A and ACAT1 expression and by increasing ABCA1 expression at both mRNA and protein levels. Heregulin-beta(1) significantly decreased endocytic uptake of [(125)I]acetylated low-density lipoprotein and ACAT activity, and increased cholesterol efflux to apolipoprotein (Apo)A-I from human macrophages. Chronic infusion of heregulin-beta(1) into ApoE(-/-) mice significantly suppressed the development of atherosclerotic lesions.


CONCLUSIONS
This study provided the first evidence that heregulin-beta(1) inhibits atherogenesis and suppresses macrophage foam cell formation via SR-A and ACAT1 downregulation and ABCA1 upregulation.
Xu
Gang
G
Department of Medicine, Division of Diabetes, Metabolism, and Endocrinology, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8666, Japan. hirano@med.showa-u.ac.jp.
Watanabe
Takuya
T
Iso
Yoshitaka
Y
Koba
Shinji
S
Sakai
Tetsuo
T
Nagashima
Masaharu
M
Arita
Shigeko
S
Hongo
Shigeki
S
Ota
Hidekazu
H
Kobayashi
Youichi
Y
Miyazaki
Akira
A
Hirano
Tsutomu
T
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000101:Acetyl-CoA C-Acetyltransferase / Q000235:genetics / Q000378:metabolism; D054058:Acute Coronary Syndrome / Q000097:blood / Q000209:etiology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000787:Angina Pectoris / Q000097:blood / Q000209:etiology; D000818:Animals; D000906:Antibodies / Q000008:administration & dosage; D016632:Apolipoprotein A-I / Q000378:metabolism; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000097:blood / Q000150:complications / Q000517:prevention & control*; D001692:Biological Transport; D015415:Biomarkers / Q000097:blood; D018955:CD36 Antigens / Q000378:metabolism; D002478:Cells, Cultured; D002788:Cholesterol Esters / Q000378:metabolism; D003324:Coronary Artery Disease / Q000097:blood / Q000150:complications / Q000517:prevention & control*; D004195:Disease Models, Animal; D015536:Down-Regulation; D004705:Endocytosis; D005260:Female; D005487:Foam Cells / Q000378:metabolism*; D006801:Humans; D006973:Hypertension / Q000097:blood; D008077:Lipoproteins, LDL / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D020890:Neuregulin-1 / Q000008:administration & dosage / Q000097:blood* / Q000276:immunology / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012421:Rupture; D051117:Scavenger Receptors, Class A / Q000235:genetics / Q000378:metabolism; D051122:Scavenger Receptors, Class B / Q000378:metabolism; D012720:Severity of Illness Index; D013997:Time Factors
C577836:ABCA1 protein, human; C505693:APOA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D000906:Antibodies; D016632:Apolipoprotein A-I; D001057:Apolipoproteins E; D015415:Biomarkers; D018955:CD36 Antigens; D002788:Cholesterol Esters; D008077:Lipoproteins, LDL; D020890:Neuregulin-1; D012333:RNA, Messenger; C495124:SCARB1 protein, human; D051117:Scavenger Receptors, Class A; D051122:Scavenger Receptors, Class B; C032629:acetyl-LDL; C117463:heregulin alpha; C087230:heregulin beta1; C506639:ACAT1 protein, human; D000101:Acetyl-CoA C-Acetyltransferase