Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.23 (MMP)
 4,246 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID: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. 1041 29

Oxidized LDL and its receptors play important roles in atherosclerotic progression and atherosclerotic plaque rupture, by enlarging the lipid core and weakening the fibrous cap. Oxidized LDL, in fact, induces foam cell transformation of macrophages, production of matrix metalloproteinases(MMPs), and apoptosis of smooth muscle cells. Oxidized LDL concentrations in circulating blood in humans have been shown to be elevated in diabetes and atherosclerotic vascular diseases, especially acute coronary syndrome. Lectin-like oxidized LDL receptor-1(LOX-1) is a cell surface receptor for oxidized LDL, which is abundantly expressed in atherosclerotic plaques and is involved in oxidized LDL-induced MMP production and apoptosis. Soluble LOX-1 concentration in human blood also have been shown to be elevated in coronary heart diseases especially in acute coronary syndrome.
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PMID:[Measurement of oxidized LDL and its soluble receptors]. 1520 53

In recent years, significant progress was made, particularly through the use of the macaque monkey, in identifying three types of local factors that are induced by the midcycle LH surge and play a critical role in ovulation and/or luteinization of the primate follicle. The ovulatory gonadotropin surge increases prostaglandin (PTG, typically abbreviated PG) levels in follicles prior to rupture; although considerable attention has focused on LH stimulation of the "inducible" form of PG G/H synthase (PTGS2), other aspects of PG synthesis (notably a phospholipase A2, cPLA2, and a PGE synthase, PTGES) and metabolism (15-hydroxy PG dehydrogenase, HPGD) also appear LH-regulated and may control the timing of the PG rise in the ovulatory follicle. Local (intrafollicular) ablation and replacement of PGs suggests that PGE2 is essential for release of the oocyte; but not necessarily for follicle rupture, and not for luteinization. Novel PGE-regulated genes are being identified in macaque granulosa cells, including adipose differentiation-related protein (ADFP). Similar types of studies indicate that the rise in progesterone (P) synthesis, as well as the induction of the genomic P receptor in granulosa cells, is essential for both ovulation and luteinization of the primate follicle. Limited data suggest that P action controls cell cycle activity (via cyclin B1 and cyclin-dependent kinase inhibitor p27), cholesterol uptake and utilization (e.g., low density lipoprotein or LDL receptor), proteases and their inhibitors (matrix metalloproteinase or MMP1; tissue inhibitor of MMP or TIMP1) and cell health in the granulosa cell layer. Finally, members of two classes of angiogenic factors, originally proposed as important for embryonic and pathologic (tumorigenic) vasculogenesis, appear induced in the granulosa layer of the preovulatory follicle, i.e., vascular endothelial growth factor (VEGF) and angiopoietin (ANGPT). Local injection of antagonists to VEGF (soluble VEGF receptor) and ANGPT (the natural antagonist ANGPT2) into the preovulatory follicle suppressed ovulation and luteinization in monkeys, possibly by disrupting the structure-function of existing vessels or preventing angiogenesis in the avascular granulosa layer. Further studies using high-throughput genomic and proteomic analysis, particularly on specific cell types (e.g., granulosa, theca and microvascular cells) and distinct follicular regions (apex, base and cumulus-oocyte complex) of the dominant follicle in natural menstrual cycles, are needed. Such information is essential to advance our understanding of the cascade of events leading to ovulation and luteinization of the primate follicle, to unravel the causes of ovary-based infertility and to consider novel ovary-selective approaches to contraception.
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PMID:Molecular control of ovulation and luteinization in the primate follicle. 1712