Renin-angiotensin System Activation And Imbalance Of Matrix Metalloproteinase-9/Tissue Inhibitor Of Matrix Metalloproteinase-1 In Renovascular Hypertensive Rats With Cold-Induced Stroke

BackgroundOur previous study has shown that cold-induced matrix metalloproteinase-9(MMP-9)upregulation might play a pivotal role in the cold-induced stroke initiation during hypertension.Cold exposure increased renin-angiotensin system(RAS)activity to enhance the expression of angiotension II(AngII).Accumulating studies show that MMP-9 is identified as vital target genes for AngII,which have been tightly tied to induce MMP-9 expression and activation.Tissue inhibitors of matrix metalloproteinase-1(TIMP-1)is the primary specific endogenous inhibitors of MMP-9.ObjectivesTo investigate the roles of RAS activation and imbalance of MMP-9/TIMP-1 in cold-induced stroke during chronic hypertension,and to assess the protective effect of captopril and recombinant human TIMP-1(rhTIMP-1).MethodsA total of 170 rats were randomly subjected to a sham group(n=20),2-kidney,2-clip(2K-2C)hypertension group,captopril-received 2K-2C group,and rhTIMP-1-received 2K-2C group(n=50 in the three groups).After the blood pressure values had stabilized,each group was randomly divided to an acute cold exposure group(12h-light at 22?/12h-dark at 4?)and a nonacute cold exposure group(12h-light/12h-dark at 22?),each of which underwent three cycles exposure.Rats were treated with captopril by gavage(50mg/kg/d)and rhTIMP-1 by tail intravenous injection(60?g/kg/36h)during exposure,respectively.ResultsThe results showed that the expression of AngII and MMP-9 increased significantly in both the plasma and cortex,while no such changes in TIMP-1 expression were observed in 2K-2C group.Cold exposure further upregulated AngII and MMP-9 protein levels in plasma and cortex and increased the stroke incidence in 2K-2C group.Captopril and rhTIMP-1 treatment prevented upregulation of MMP-9 expression and activation in response to cold exposure and decreased stroke incidence.ConclusionThe present study firstly demonstrate that cold exposure exacerbated MMP-9/TIMP1 imbalance via activation of RAS might play a critical role in the initiation of cold-induced stroke during chronic hypertension,captopril and rhTIMP-1 exert protective effects against cold-induced stroke through ameliorating MMP-9/TIMP-1 imbalances.