Effect of matrix metalloproteinase inhibition on progression of atherosclerosis and aneurysm in LDL receptor-deficient mice overexpressing MMP-3, MMP-12, and MMP-13 and on restenosis in rats after balloon injury.
The broad-spectrum MMP inhibitor CGS 27023A was tested to determine its potential as a therapy for atherosclerosis, aneurysm, and restenosis. LDL receptor-deficient (LDLr -/-) mice fed a high-fat, cholic acid-enriched diet for 16 weeks developed advanced aortic atherosclerosis with destruction of elastic lamina and ectasia in the media underlying complex plaques. Lesion formation correlated with a 4.6- to 21.7-fold increase in MMP-3, -12, and -13 expression. Treatment with CGS 27023A (p.o., b.i.d. at 50 mg/kg) had no effect on the extent of aortic atherosclerosis (36 +/- 4% versus 30 +/- 2% in controls), but both aortic medial elastin destruction and ectasia grade were significantly reduced (38% and 36%, respectively, p < 0.05). In the rat ballooned-carotid-artery model, CGS 27023A (12.5 mg/kg/day via osmotic minipump) reduced smooth muscle cell migration at 4 days by 83% (p < 0.001). Intimal lesions were reduced by 85% at 7 days (p < 0.001), but intimal smooth muscle proliferation was unaffected, and inhibitory efficacy was lost with time. At 12 days, intimal lesion reduction was less potent (52%, p < 0.01). At 3 and 6 weeks, reductions of 11% and 4%, respectively, were not significant. This demonstrates that it is essential to include late time points when the ballooned-carotid-artery model is employed to ensure that lesion size does not "catch up" when a compound solely inhibits smooth muscle cell migration. In summary, MMP inhibitor therapy delayed but did not prevent intimal lesions, thereby demonstrating little promise to prevent restenosis. In contrast, MMP inhibitor therapy may prove useful to retard progression of aneurysm.
Metabolic and Cardiovascular Research Department, Novartis Institute for Biomedical Research, Summit, New Jersey 07901, USA. margaret.prescott@pharma.novartis.com
M F
MF
Prescott
W K
WK
Sawyer
J
J
Von Linden-Reed
M
M
Jeune
M
M
Chou
S L
SL
Caplan
A Y
AY
Jeng
D000818:Animals; D001012:Aorta, Abdominal / Q000473:pathology / Q000503:physiopathology; D017544:Aortic Aneurysm, Abdominal / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D001161:Arteriosclerosis / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology*; D002339:Carotid Arteries / Q000473:pathology / Q000503:physiopathology*; D020212:Carotid Artery Injuries; D002404:Catheterization; D002465:Cell Movement; D017364:Collagenases / Q000235:genetics*; D004549:Elastin / Q000378:metabolism; D006877:Hydroxamic Acids; D008297:Male; D053508:Matrix Metalloproteinase 12; D053509:Matrix Metalloproteinase 13; D019278:Matrix Metalloproteinase 3 / Q000235:genetics*; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors* / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D011480:Protease Inhibitors / Q000494:pharmacology*; D011719:Pyrazines; D051381:Rats; D017207:Rats, Sprague-Dawley; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D012008:Recurrence; D013449:Sulfonamides; D014158:Transcription, Genetic
C097658:CGS 27023A; D006877:Hydroxamic Acids; D011480:Protease Inhibitors; D011719:Pyrazines; D011973:Receptors, LDL; D013449:Sulfonamides; D004549:Elastin; D017364:Collagenases; D053509:Matrix Metalloproteinase 13; D008666:Metalloendopeptidases; C507081:Mmp13 protein, mouse; C507083:Mmp13 protein, rat; D019278:Matrix Metalloproteinase 3; D053508:Matrix Metalloproteinase 12