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

Abstract

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.

The dynamic extracellular matrix: intervention strategies during heart failure and atherosclerosis

“…Temporal gene expression profiles in a rat carotid artery injury model showed a tight regulation of MMP expression and genes that modulate MMP expression [63]. This time window is also reflected by the results of the above-mentioned MMP inhibition study, in which decreased early neo-intima formation had no long-term effect [62]. In a mouse carotid ligation model, MMP-9 deficiency decreased intimal hyperplasia, reduced the late lumen loss, and led to a significant accumulation of interstitial collagen [64].…”

“…Inhibition of MMPs by either a synthetic MMP inhibitor or overexpression of TIMPs decreases neo-intima formation. One MMP inhibition study showed a decrease in early neo-intima formation, while long-term effects were not observed [62]. Temporal gene expression profiles in a rat carotid artery injury model showed a tight regulation of MMP expression and genes that modulate MMP expression [63].…”

“…In models of aneurysm formation, results of genetic and pharmacological interventions are quite clear (Table 2). Deficiency in MMP-3 [65] and MMP-9 [66] gene expression or general inhibition of MMPs [62,67] led to a decrease in aneurysm formation or inhibited aneurysm rupture. Only MMP-12 deficiency rendered no effect on aneurysm formation MMP, matrix metalloproteinase; Apo, apolipoprotein; LDLR, LDL receptor; TIMP, tissue inhibitor of matrix metalloproteinase; SMC, smooth muscle cell; TGF, transforming growth factor; +/+, transgenic overexpressing mice; −/−, knock-out or homozygous deficient mice; ↑, upregulation or increased; ↓, downregulated or decreased.…”

“…Overexpression of MMP-1 resulted in a decreased plaque size in ApoE knock-out mice [70], MMP-3 deficiency increased plaque size and progression in ApoE knock-out mice [65], while the genetic variation in the human MMP-3 promoter also was correlated with plaque progression [71]. Broad-range MMP inhibitors, however, had no effect on plaque size in LDL receptor-deficient mice [62]. Contrasting results were obtained for MMP-9 overexpression [48,72]; thus Zhang et al showed that patients with functional polymorphisms in the regulatory region of the gelatinase B gene (=MMP-9) suffered more frequently from coronary triple vessel disease [48].…”

Role of multidomain structure of urokinase in regulation of growth and remodeling of vessels

“…Вовлечение системы матриксных металло-протеиназ в процесс заживления раны после баллонного повреждения доказывает и тот факт, что увеличение экспрессии ингибитора ММп -тiМр-1 подавляет развитие неоин-тимы [146], в то время как у мышей с дефи-цитом тiМр-1 образование неоинтимы после электрического повреждения бедренной арте-рии было более выраженным. использование различных ингибиторов ММп приводило к Biochemistry aNd BiotechNology for moderN mediciNe замедлению образования неоинтимы и по-давлению миграции гладкомышечных клеток [147]. известно также, что между фибриноли-тической системой (системой активаторы плаз-миногена-плазмин) и системой матриксных металлопротеиназ существует тесное функцио-нальное взаимодействие [139,144].…”