Owens M W, Milligan S A, Jourd'heuil D, Grisham M B
Department of Medicine, Overton Brooks Veterans Affairs, Shreveport, Louisiana, USA.
Am J Physiol. 1997 Aug;273(2 Pt 1):L445-50. doi: 10.1152/ajplung.1997.273.2.L445.
The regulation of matrix metalloproteinase activity is crucial for maintaining the proper balance of tissue remodeling vs. injury. Metalloproteinase proenzymes are activated when the active site zinc is exposed via a cysteine switch mechanism. Peroxynitrite, the product generated from the interaction between nitric oxide and superoxide, has been shown to release zinc from zinc-thiolate groups, suggesting that it might alter metalloproteinase activity. This study examined the effects of nitric oxide and superoxide generators on gelatinase A activity. Results showed that nitric oxide alone had no effect on gelatinase A activity relative to control, whereas superoxide-derived metabolites increased activity. The simultaneous generation of both nitric oxide and superoxide caused an inhibition of gelatinase A activity. This inhibition was reversed by the addition of hemoglobin, superoxide dismutase, or sodium urate, suggesting that peroxynitrite and/or peroxynitrous acid caused the inhibition. Authentic peroxynitrite also inhibited gelatinase A activity. We postulate that the relative fluxes of nitric oxide and superoxide at sites of inflammation may modulate metalloproteinase activity and thus affect matrix protein metabolism.
基质金属蛋白酶活性的调节对于维持组织重塑与损伤之间的适当平衡至关重要。当活性位点锌通过半胱氨酸开关机制暴露时，金属蛋白酶原酶被激活。一氧化氮和超氧化物相互作用产生的产物过氧亚硝酸盐已被证明能从硫醇锌基团中释放锌，这表明它可能会改变金属蛋白酶的活性。本研究考察了一氧化氮和超氧化物生成剂对明胶酶A活性的影响。结果显示，相对于对照组，单独的一氧化氮对明胶酶A活性没有影响，而超氧化物衍生的代谢产物则增加了活性。一氧化氮和超氧化物同时生成会导致明胶酶A活性受到抑制。添加血红蛋白、超氧化物歧化酶或尿酸钠可逆转这种抑制作用，这表明过氧亚硝酸盐和/或过亚硝酸导致了这种抑制。纯过氧亚硝酸盐也抑制明胶酶A活性。我们推测，炎症部位一氧化氮和超氧化物的相对通量可能会调节金属蛋白酶的活性，从而影响基质蛋白代谢。
