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

Autor: Michael Jeune, Shari L. Caplan, Mary Chou, Jean Von Linden-Reed, Margaret F. Prescott, Arco Y. Jeng, W. K. Sawyer
Rok vydání: 1999
Předmět:
Male
medicine.medical_specialty
Pathology
Smooth muscle cell migration
Transcription
Genetic
Arteriosclerosis
Hydroxamic Acids
General Biochemistry
Genetics and Molecular Biology
Catheterization
Lesion
Rats
Sprague-Dawley
Aortic aneurysm
Mice
History and Philosophy of Science
Restenosis
Cell Movement
Recurrence
medicine.artery
Internal medicine
Matrix Metalloproteinase 12
Matrix Metalloproteinase 13
medicine
Animals
Protease Inhibitors
Aorta
Abdominal
Collagenases
Aortic atherosclerosis
Mice
Knockout
Aorta
Sulfonamides
biology
business.industry
General Neuroscience
Metalloendopeptidases
medicine.disease
Elastin
Rats
Endocrinology
Carotid Arteries
Receptors
LDL
Pyrazines
LDL receptor
biology.protein
Matrix Metalloproteinase 3
medicine.symptom
business
Carotid Artery Injuries
Aortic Aneurysm
Abdominal
Zdroj: Annals of the New York Academy of Sciences. 878
ISSN: 0077-8923
Popis: 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.
Databáze: OpenAIRE
Externí odkaz: