Experimental Study In Prevention Of Cardiovascular Diseases By Interfering Nuclear Factor κβ Activation With Simvastatin

Nuclear factor-κB (NF-κB) is a nuclear transcription factorexisted in all the cells,which plays an important role in the regulationof many inflammatory genes expression participated in thedevelopment of many cardiovascular diseases,such as atherosclerosis(AS),ischemia-reperfusion injury,post-infarct ventricular remodeling,ventricular hypertrophy,etc.Statins have pleiotropic effects associated with their benefits formany cardiovascular diseases,such as having a role in anti-atherosclerosis,decreasing ischemia-reperfusion injury,attenuating postinfarctventricular remodeling,ameliorating ventricular hypertrophy,etc.Interference with NF-κB activation by statins might be one of themechanisms of their pleiotropic effects.However,interference withNF-κB activation by statins affecting inflammatory factors expressionin THP-1 mononuclear cells and ventricular hypertrophy induced bypressure overload was not fully clarified.In the present study,interference with NF-κB activation by simvastatin affectinginflammatory factors expression in THP-1 mononuclear cells andventricular hypertrophy induced by pressure overload was investigated,from which further mechanisms were provided to us to understandpleiotropic effects of statins. Partâ… Effect of Simvastatin on the MonocyteChemoattractant Protein-1 Expression and NuclearFactor-κB Activation Induced by Lipopolysaccharidein Human THP-1 Mononuclear Cell and MechanismObjective:To study the effect of simvastatin on the monocytechemoattractant protein-1 (MCP-1) expression and nuclear factor-κB(NF-κB) activation induced by lipopolysaccharide (LPS) in humanTHP-1 mononuclear cell,the mechanism of simvastatin in regulationof the MCP-1 expression and NF-κB activation in monocyte in aninflammatory situation was investigated.Methods:The human THP-1 mononuclear cell line was culturedand divided into five groups as control group,LPS group,and low,moderate or high dose simvastatin groups.After pre-incubated withdifferent concentration (1,5 and 10μmol/L) simvastatin for 2h,thethree simvastatin groups and LPS group were stimulated with LPS for24h.IκB-a,NF-κBP⁶⁵ and MCP-1 in cytosolic extract and NF-κBp⁶⁵ innuclear extract of each group were measured by western blot;MCP-1in supernatant of each group was measured by ELISA.Results:Simvastatin prevented MCP-1 increase in human THP-1mononuclear cell induced by LPS in a dose dependent manner;and itprevented IκB-a and NF-κBp⁶⁵ decrease in cytosolic extract andNF-κBP⁶⁵ increase in nuclear extract in the same way.Conclusion:Suppression of the MCP-1 expression in humanTHP-1 mononuclear cell induced by LPS by simvastatin maybeattributed to its inhibitory effect on NF-κB activation;simvastatinappears to prevent NF-κB activation by preventing the degradation of IκB-a.Partâ…¡Relationship Between Inhibitory Effect ofSimvastatin on Matrix Metalloproteinase-9Expression in Human THP-1 Mononuclear CellInduced by LPS and Activation of NF-κBObjective:To study the effect of simvastatin on the matrixmetalloproteinase-9 (MMP-9) expression and nuclear factor-κB(NF-κB) activation induced by lipopolysaccharide (LPS) in humanTHP-1 mononuclear cell,the mechanism of simvastatin in regulationof MMP-9 expression in monocyte in an inflammatory situation wasinvestigated.Methods:The human THP-1 mononuclear cell was cultured anddivided into five groups as control group,LPS group,and low,moderate or high dose simvastatin groups.After pre-incubated withdifferent concentration simvastatin for 2h,the three simvastatingroups and LPS group were stimulated with LPS for 24h.MMP-9 incytosolic extract and supernatant of each group was measured bywestern blot and ELISA,respectively;IκB-a in cytosolic extract andNF-κB p⁶⁵ in nuclear extract of each group was measured by westernblot and ELISA,respectively.Results:Simvastatin prevented MMP-9 increase in cytosolicextract and supernatant in human THP-1 mononuclear cell induced byLPS in a dose dependent manner;and it prevented IκB-a decrease incytosolic extract and NF-κBP⁶⁵ increase in nuclear extract in the sameway.Conclusion:Suppression of the MMP-9 expression in human THP-1 mononuclear cell induced by LPS by simvastatin maybeattributed to its inhibitory effect on NF-κB activation;which suggestsit has a role in plaque stabilization.Partâ…¢Inhibition of NF-κB Activation inMyocardium in Rats with Pressure Overload bySimvastatin Attenuates Myocardial HypertrophyObjective:To study the effect of simvastatin (Sim) on NF-κBactivation in myocardium in rats with pressure overload and itsrelation to myocardial hypertrophy (MH),the mechanism in MHattenuated by Sim was investigated.Methods:32 rats were divided into 4 groups,(1) MH group,onlybanding of ascending aorta;(2) PDTC group,banding of ascendingaorta and injected intraperitoneally with PDTC 80 mg/(kg·d);(3) Simgroup,banding of ascending aorta and gavage with Sim 40 mg/(kg·d);(4) Sham group,no banding of ascending aorta.After 2 weeks,theratio of left ventricular weight to body weight was calculated,p-IκB-aand IκB-a levels in myocardial homogenate were measured by westernblot and NF-κBp⁶⁵ levels in myocardial homogenate was assessed byELISA.Results:Compared with sham group,the ratio of left ventricularweight to body weight were significantly increased in MH group,andp-IκB-a was obviously increased,IκB-a was markedly decreased andNF-κBp⁶⁵ was apparently increased in myocardial homogenate;However,both PDTC and Sim could prevent the ratio of leftventricular weight to body weight increased induced by aorta banding,and they could inhibit p-IκB-a obviously increased,IκB-a markedly decreased and NF-κBp⁶⁵ apparently increased in myocardialhomogenate.Conclusion:NF-κB activation might be involved in MH in ratswith pressure overload induced by aorta banding;Sim had aninhibitory effect on MH in rats with pressure overload induced by aortabanding,which might be associated with its inhibition of NF-κBactivation.