Functional interplay between the macrophage scavenger receptor class B type I and pitavastatin (NK-104).
BACKGROUND
Scavenger receptor class B type I (SR-BI), a receptor for high-density lipoprotein (HDL), plays an important role in the bidirectional cholesterol exchange between cells and HDL particles and the atherosclerotic lesion development. Enhancement of SR-BI expression significantly reduces, whereas lack of SR-BI expression accelerates, the atherosclerotic lesion development in proatherogenic mice. Statins, a class of inhibitors for 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, significantly suppress de novo cholesterol synthesis and reduce the incidence of coronary heart disease. Statins also display multiple pleiotropic effects independently of cholesterol synthesis in the vascular cells. Here, we investigated the effects of pitavastatin (NK-104), a newly synthesized statin, on macrophage SR-BI expression.


RESULTS
We found that pitavastatin significantly increased SR-BI mRNA and protein expression in a macrophage cell line in a concentration- and time-dependent manner. It also increased SR-BI expression in both mouse peritoneal and human monocyte-derived macrophages. Associated with increased SR-BI expression, pitavastatin enhanced macrophage HDL binding, uptake of [14C]cholesteryl oleate/HDL, and efflux of [3H]cholesterol to HDL. Pitavastatin abolished the inhibition of macrophage SR-BI expression by cholesterol biosynthetic intermediates. It also restored SR-BI expression inhibited by lipopolysaccharide and tumor necrosis factor-alpha through its inactivation of the transcription factor nuclear factor-kappaB.


CONCLUSIONS
Our data demonstrate that pitavastatin can stimulate macrophage SR-BI expression by reduction of cholesterol biosynthetic intermediates and antiinflammatory action and suggest additional pleiotropic effects of statins by which they may reduce the incidence of coronary heart disease.
Han
Jihong
J
Center of Vascular Biology and Department of Pathology, Weill Medical College of Cornell University, 1300 York Ave, New York, NY 10021, USA. jhan@med.cornell.edu
Parsons
Michael
M
Zhou
Xiaoye
X
Nicholson
Andrew C
AC
Gotto
Antonio M
AM
Hajjar
David P
DP
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D018955:CD36 Antigens; D002460:Cell Line / Q000187:drug effects / Q000378:metabolism; D002784:Cholesterol / Q000096:biosynthesis; D002788:Cholesterol Esters / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D020672:I-kappa B Proteins / Q000096:biosynthesis / Q000235:genetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D009570:Nitriles / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D011971:Receptors, Immunologic / Q000096:biosynthesis* / Q000235:genetics; D018110:Receptors, Lipoprotein / Q000096:biosynthesis* / Q000235:genetics; D051116:Receptors, Scavenger; D051122:Scavenger Receptors, Class B; D013268:Stimulation, Chemical; D013450:Sulfones / Q000494:pharmacology; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D000894:Anti-Inflammatory Agents, Non-Steroidal; C416282:BAY 11-7085; D018955:CD36 Antigens; D002788:Cholesterol Esters; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D020672:I-kappa B Proteins; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D016328:NF-kappa B; D009570:Nitriles; D010455:Peptides; D011804:Quinolines; D012333:RNA, Messenger; D011971:Receptors, Immunologic; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; C495124:SCARB1 protein, human; C118258:SN50 peptide; C454739:Scarb1 protein, mouse; D051122:Scavenger Receptors, Class B; D013450:Sulfones; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D002784:Cholesterol; C108475:pitavastatin