[New insights on the molecular mechanisms of type-1 angiotensin II receptor blockers and their contribution to atherosclerotic plaque stabilization].
Clinical trials have demonstrated that agents inhibiting the angiotensin II pathway confer benefit beyond the reduction of blood pressure alone. However, the molecular mechanism underlying this effect has yet to be investigated. Recently, we have demonstrated enhanced expression of inducible COX and PGE synthase (COX-2/mPGES-1) in human symptomatic plaques, and provided evidence that it is associated with plaque rupture induced by metalloproteinases (MMPs), proteolytic enzymes of matrix structural components. In a recent study, we hypothesized that angiotensin II could promote plaque instability through induction of the COX-2/mPGES-1 pathway. We analyzed atherosclerotic plaques from symptomatic patients who were randomized to treatment with irbesartan (300 mg/die) or chlortalidone (50 mg/die) for 4 months before endarterectomy. We found that plaques from the irbesartan group had reduced inflammatory infiltration, less immunoreactivity for COX-2/mPGES-1 and MMPs, reduced gelatinolytic activity and increased collagen content. It is worth noting that COX-2/mPGES-1 inhibition was observed after incubation in vitro with irbesartan but not with the selective AT2 blockade PD123,319. These findings suggest that AT1 receptor blockers could represent a novel form of therapy for plaque stabilization in patients with atherosclerotic disease.
Mezzetti
Andrea
A
Fazia
Maria
M
Cipollone
Francesco
F
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology / Q000627:therapeutic use*; D000959:Antihypertensive Agents / Q000627:therapeutic use; D001161:Arteriosclerosis / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology / Q000601:surgery; D001713:Biphenyl Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D002752:Chlorthalidone / Q000627:therapeutic use; D051546:Cyclooxygenase 2; D004691:Endarterectomy; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000187:drug effects* / Q000378:metabolism; D000077405:Irbesartan; D020778:Matrix Metalloproteinase 2 / Q000187:drug effects; D020780:Matrix Metalloproteinase 9 / Q000187:drug effects; D008565:Membrane Proteins; D045726:Metalloproteases / Q000187:drug effects* / Q000378:metabolism; D000071876:Prostaglandin-E Synthases; D011451:Prostaglandin-Endoperoxide Synthases / Q000187:drug effects* / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology / Q000627:therapeutic use*
D047228:Angiotensin II Type 1 Receptor Blockers; D000959:Antihypertensive Agents; D001713:Biphenyl Compounds; D008565:Membrane Proteins; D013777:Tetrazoles; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D045726:Metalloproteases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D019746:Intramolecular Oxidoreductases; C000605862:PTGES protein, human; D000071876:Prostaglandin-E Synthases; D000077405:Irbesartan; D002752:Chlorthalidone