The Experimental Study Of Losartan On Reversing Ventricular Remodeling And Underlying Mechanism

Ventricular remodeling（VR） is changed ventricular structure, which includes hypertro-phic cardiomyocytes,interstitial cell （cardiofibroblasts, CFb） proliferation and collagen tissuehyperplasia.LVR induced by cardiac fibrosis means geometric variation of left ventricle,thatis the increase of cardiac volume and mass. It can be classified by elevated collagen volumefraction （CVF） than normal tissues.VR is triggered by collagen anabolism and catabolism balance disorders in Macroscopicview. The occurrence of VR is related to many factors,briefly, its formation mechanism andadjusting mechanisms are more complex, activation of neuroendocrine system is one of themain leading mechanisms of VR deterioration.Studies show that in VR caused by manyfactors, the RAAS system plays an important role, which led to angiotensin II that is animportant factor in the increase in myocardial collagen, AngII binds with AT₁receptor andactivate PKC, MAPK transduction pathway, transcription factors, promoting myocardial celland CFb to autocrine and paracrine many fiber growth factors, such as ET-1,、TGF-β1,、CTGF etc.Losartan （Losartan, Lor） reverses ventricular remodeling and myocardial fibrosis whichhave been confirmed, but its mechanism especially molecular biology and signal transductionmechanism is not completely clear. from the in vivo and in vitro two aspects This topic aimsto explore the effect of Lor on VR and the detailed mechanism, designing to elucidate itsmechanisms for reversal of VR, the major targets for drug intervention, the drug in the furtherclinical application and development of new anti-VR drugs to lay the foundation.The mainresearch steps are as follows:1the application of Iso induced rat model of VR, which wasobserved after the administration of Lor’s influence on VR; The histopathology techniques was adopted through HE、Masson、TE、IH staining, Western blot etc.to observe themorphology of the rat, myocardial hypertrophy index and TGF-β₁, p-PKCα expression underLor intervention.The results showed that Lor markedly inhibited Iso induced VR phenomenon;reduced the synthesis of collagen hydroxyproline content; reduced o p-PKCα and TGF-β1protein expression. in myocardial tissue.2CFb were cultured in vitro, the Ang â…¡-inducedproliferation of CFb.Using an inverted microscope, MTT and flow cytometer to observe theEffect of losartan on cell proliferation and cell cycle.Western blot for Lor on CFb p27kip1Protein Expression in rats.The results showed that: Lor can inhibit the proliferation of CFb,cell cycle arrested in G0/G1phase; increased cyclin dependent kinase inhibitor （CDKI） on theexpression of p27kip1in a dose-dependent manner.3CFb cells were cultured in vitro, theexpression of p-PKCα and the expression of TGF-β1were observed in Western blotdetection for Lor. The results showed that: Lor can inhibit signal transduction molecules ofp-PKCα, p-PKCα protein activity; down-regulate TGF-β₁expression.Indicating that the Lorantagonistic effect of VR by decreasing p-PKCα activity so as to reduce the expression ofTGF-β1.