Macrophages: An elusive yet emerging therapeutic target of atherosclerosis

Rajiv Lochan Tiwari, Vishal Singh, Manoj Kumar Barthwal

Research output: Contribution to journalReview article

111 Citations (Scopus)

Abstract

Macrophages are central to the initiation and progression of atherosclerosis and thus can be very appropriate targets for therapy. Cell adhesion molecules mediating monocytes recruitment to the endothelium are attractive therapy targets and their inhibitors are in clinical trials. Macrophage scavenger receptors like SR-A and CD-36 mediate foam cell formation by facilitating the uptake of modified lipids. Peroxisome proliferator-activated receptors (PPAR), liver X receptor (LXR)-mediated signaling, mitogen-activated protein kinase (MAPK) induced phosphorylation events seem to play an important role in this phenomenon. Proteins affecting macrophage cholesterol metabolism and transport, including ATP-binding cassette (ABC) A1, ABCG1, acyl-CoA:cholesterol acyltransferase (ACAT), apolipoprotein A-1 (ApoA-1), neutral cholesteryl ester hydrolase (NCEH) also regulate foam cell formation and are being developed as therapeutic targets by many pharmaceutical companies. Macrophage proliferation and apoptosis are important events controlling inflammatory response, plaque vulnerability, and destabilization. Free cholesterol (FC) activates the macrophage endoplasmic reticulum (ER) stress pathway and apoptosis. Free radicals and nitric oxide also modulate macrophage foam cell formation and apoptosis. Various antioxidants like AGI-1067 and BO-653 are in clinical trials for atherosclerosis treatment. Macrophage matrix metalloproteinase's (MMP's) play a significant role in weakening and rupture of plaques. Efforts are on to develop isoform specific MMP inhibitor. CD-14, MMP-3, ABCA1, Toll-like receptor-4 (TLR-4), lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), arachidonate lipoxygenase-15 (ALOX-15), and Connexin37 polymorphisms and macrophage dysfunction signify their importance in atherosclerosis. Deciphering the role of macrophages in regulating dyslipidemia and inflammation during atherosclerosis is important for developing them as therapeutic targets.

Original languageEnglish (US)
Pages (from-to)483-544
Number of pages62
JournalMedicinal Research Reviews
Volume28
Issue number4
DOIs
StatePublished - Jul 1 2008

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Atherosclerosis
Macrophages
Foam Cells
Therapeutics
Apoptosis
Class E Scavenger Receptors
Cholesterol
Clinical Trials
Arachidonate 15-Lipoxygenase
Sterol O-Acyltransferase
Scavenger Receptors
Matrix Metalloproteinase 3
Peroxisome Proliferator-Activated Receptors
Toll-Like Receptor 4
Endoplasmic Reticulum Stress
Matrix Metalloproteinase Inhibitors
Cholesterol Esters
Apolipoprotein A-I
Cell Adhesion Molecules
Hydrolases

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology
  • Drug Discovery

Cite this

Tiwari, Rajiv Lochan ; Singh, Vishal ; Barthwal, Manoj Kumar. / Macrophages : An elusive yet emerging therapeutic target of atherosclerosis. In: Medicinal Research Reviews. 2008 ; Vol. 28, No. 4. pp. 483-544.
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Macrophages : An elusive yet emerging therapeutic target of atherosclerosis. / Tiwari, Rajiv Lochan; Singh, Vishal; Barthwal, Manoj Kumar.

In: Medicinal Research Reviews, Vol. 28, No. 4, 01.07.2008, p. 483-544.

Research output: Contribution to journalReview article

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