| BackgroundMyocardial fibrosis (MF) is a process of metabolic imbalance of myocardial collagen synthesis and degradation,manifested as myocardial interstitial collagen deposition increased and the proportion of various types disordered, which is one of the main manifestations of the hypertensive left ventricular remodeling and may lead to the increasion of myocardial stiffness, diastolic dysfunction, further,left ventricular systolic dysfunction,and even some serious complications,such as heart failure, arrhythmia and sudden cardiac death,etal. Therefore, MF is a serious threat to public health.Previous studies had shown that the formation of myocardial fibrosis in hypertension involved in renin-angiotensin-aldosterone system(RAAS),etal,and closely related factors including Angiotensin II (Ang II), transforming growth factor-β1 (TGF-β1), endothelin and interleukin-1 (IL-1),etal. In recent years, studies have shown that inflammation and hypertension mutual influence,and are each other's results. The inflammatory process could be in reality an immune specific process in the development of hypertension. Hinglais confirmed that collagen fibers in cardiac interstitium increased, inflammatory cells and fibroblasts co-existed in the area of myocardial fibrosis,and fibrosis area was related to the density of interstitial macrophage infiltration in spontaneous hypertension rat. But the specific mechanisms of the role of inflammation in the process of the hypertensive myocardial fibrosis is not clear up to now. So, studying the role of the inflammatory factors in hypertensive myocardial fibrosis and the intervention has important significance,and it can contribute to inhibit the hypertensive myocardial fibrosis.In recent years, fibroblast growth factor-inducible 14(Fn14) and it's ligand-tumor necrosis factor-like weak inducer of apoptosis(TWEAK) have drawed the attention of the scholars because of their's pro-inflammatory role. Fnl4 is a member of the tumor necrosis factor (TNF) receptor superfamily and a type I transmember protein,and highly expressed in heart and kidney. Fn14 switches series of signal transduction pathway, initiation homologous gene activation by linking different receptor proteins with TRAF(TNF receptor associated factor) structure domain or intracytoplasm protein. TWEAK is a member of TNF superfamily, and a type II transmember protein,but can be cleaved to generate a 18kDa soluble factor with biological activity.Fn14/TWEAK has pleitropic biological effects to induce apoptosis and cytotoxicity, proliferation and angiogenesis.New researches show that as TWEAK's majar recepter, Fn14 could induce the expression of cytokine and inflammation through some complex signal transduction pathways.Otherwise,the studys about Fnl4/TWEAK in hypertensive myocardial fibrosis are little.Recently, studies have supported the concept of possible anti-inflammatory effects of perindopril.Objectives:These fingings provided valuable information in further understanding of Fn14/TWEAK signal transduction pathways in hypertensive myocardial fibrosis, which may ultimately lead to recognize more clearly mechanism of myocardial fibrosis.Taken together, the intervention effect of perindopril in hypertensive myocardial fibrosis early was.reserched.Methods:18 five-week SHR and the same old WKY rats were fed for one week adaptively. One week later,18 six-week-old male SHR were randomly divided into SHR-C group (SHR-C)and SHR-P group(SHR-P),and another 9 six-week-old male Wistar Kyoto rats were recruited as the healthy control (WKY). The rats in SHR-P group were treated with perindopril(produced in shiweiya,tianjin,China)(3mg/kg.d) for 24 weeks.Meanwhile, the rats in SHR-C group and WKY group were treated with double-distilled water for the same time. We took weekly measurements of rat weight and blood pressure up to the 30th week. Echocardiographic scan was performed in each group at the beginning and ending of the experiment. The measurements included end-diastolic interventricular septal thickness (IVSTd), end-systolic interventricular septal thickness(IVSTs); end-diastolic thickness of left ventricular posterior wall(LVPWTd), end-systolic thickness of left ventricular posterior wall(LVPWTs);left ventricular end-diastolic diameter(LVEDD),left ventricular end-systolic diameter(LVESD),and ejection fraction(EF), fractional shortening(FS) Integrated backscatter (IBS) parameters inclued peak to peak intensity(PPI),the average image intensity(AII) and corrected acoustic intensity(CAI). After 24 weeks, the rats were killed, and heart weight was measured to calculate the left ventricular mass index (LVMI). The histopathology change of heart tissues was observed by light microscope. Measuring the expression of collagen fibers by masson staining. The expression of Fn14, Tweak and TGF-β1 were evaluated by immunohistochemical technique. The expression of Fn14mRNA, TweakmRNA and TGF-β1mRNA in heart tissues were analyzed by real-time quantitative PCR.Results:1. The blood pressure and body weight in ratsAt six weeks of age,when compared with rats in WKY group, the systolic and diastolic blood pressures from SHR-C group and SHR-P group showed increased (P <0.05); however, compared with rats in SHR-C group and SHR-P group, there is no significant difference about the systolic and diastolic blood pressures(P>0.05). At thirty weeks of age, compared with rats in WKY group, the systolic blood pressures from SHR-C group significantly increased (P<0.01), but these from SHR-P group had no significant difference(P>0.05). Compared with rats in WKY group, the diastolic blood pressures from SHR-C group and SHR-P group showed increased (P <0.01);compared with rats in SHR-C group, the systolic and diastolic blood pressures from SHR-P group showed decreased (P<0.01),but the diastolic blood pressures increased in comparation of that form rats in WKY group. Compared with rats in WKY group,the body weight form SHR-C group and SHR-P group remarkably decresed.2. left ventricular hypertrophy in ratsAt six weeks of age,when compared with rats in WKY group, the IVSTd and LVPWTd from SHR-C group and SHR-P group showed increased (P<0.05); however, compared with rats in SHR-C group and SHR-P group, there is no significant difference about the IVSTd and LVPWTd (P>0.05).After 24 weeks, compared with rats in WKY group, the IVSTd and LVPWTd from SHR-C group and SHR-P group increased (P<0.05),and LVEDD decresed(P<0.05). Compared with rats in SHR-C group, the IVSTd and LVPWTd from SHR-P group decreased (P <0.05),and LVEDD incresed(P<0.05).The LVMI from SHR-C group significantly increased, in comparation of that form rats in WKY group(P<0.01).And the LVMI from SHR-P group significantly decreased, in comparation of that form rats in SHR-C group(P<0.01).3. systolic and diastolic dysfunction of heart in ratsAt six weeks of age, there is no significant difference about the E peaks and E/A(P>0.05). After 24 weeks, compared with rats in WKY group, E peaks and E/A from SHR-C group showed remarkably decreased (P<0.01);and the E peaks and E/A from SHR-P group significantly improved in comparation of that form rats in SHR-C group. The EF and FS from every group had no significant difference.4. IBS parameters in ratsAt six weeks of age, there is no significant difference about the AII,CAI and PPI(P>0.05). At thirty weeks of age, compared with the WKY group, All and CAI at interventricular septum and left ventricular lateral wall in SHR-C group rats were significantly increased(P<0.01), while PPI was significantly decreased(P<0.01); the All and CAI in SHR-P group rats were decreased while PPI in SHR-P group rats was increased compared with the SHR-C group(P<0.05).5. Patho-manifestation by HE in heart tissuesWhen compared with rats in WKY group and SHR-P group, the heart tissues from SHR-C group showed heart myocytes hypertrophy, the nucleus oval-shaped and increased, cytoplasm strongly stained;and some fibroblasts in heart tissues.6,Masson staining results in ratsCompared with rats in WKY group,the expression of collagen fibers form rats in SHR-C group and SHR-P group significantly incresed(P<0.01), and in comparation of rats in SHR-C group, the expression of collagen fibers form rats in SHR-P group remarkably decresed (P<0.01).7. Expression of Fn14 by immunohistochemistry in ratsCompared with rats in WKY group,the expression of Fn14 form rats in SHR-C group and SHR-P group significantly incresed(P<0.01), and in comparation of rats in SHR-C group, the expression of Fn14 form rats in SHR-P group remarkably decresed (P＜0.01).8. Expression of TWEAK by immunohistochemistry in ratsCompared with rats in WKY group,the expression of TWEAK form rats in SHR-C group and SHR-P group significantly incresed(P<0.01), and in comparation of rats in SHR-C group, the expression of TWEAK form rats in SHR-P group remarkably decresed (P<0.01).9. Expression of TGF-β1 by immunohistochemistry in ratsCompared with rats in WKY group,the expression of TGF-β1 form rats in SHR-C group and SHR-P group significantly incresed(P<0.01), and in comparation of rats in SHR-C group, the expression of TGF-β1 form rats in SHR-P group remarkably decresed (P<0.01).10,Expression of Fn14mRNA in ratsIn comparation of rats in WKY group, Fn14mRNA form rats in SHR-C group and SHR-P group were significantly high expressed(P<0.01); while compared with rats in SHR-C group, Fn14mRNA form rats in SHR-P group were remarkably low expressed(P<0.01).11,Expression of TWEAKmRNA in ratsIn comparation of rats in WKY group, TWEAKmRNA form rats in SHR-C group and SHR-P group were significantly high expressed(P<0.01); while compared with rats in SHR-C group, TWEAKmRNA form rats in SHR-P group were remarkably low expressed(P<0.01).12,Expression of TGF-β1mRNA in ratsIn comparation of rats in WKY group, TGF-β1mRNA form rats in SHR-C group and SHR-P group were significantly high expressed(P<0.01); while compared with rats in SHR-C group, TGF-β1mRNA form rats in SHR-P group were remarkably low expressed(P<0.01).13,The relationship between the expression of Fn 14,collagen fibers and TGF-β1The Fn14 expression has positive correlation with collagen fibers in heart tissue (r=0.897, P<0.01).Meanwhile, the Fn14 expression has positive correlation with TGF-β1 expression in heart tissue (r=0.862, P<0.01)14,The relationship between the expression of TWEAK,collagen fibers and TGF-β1The TWEAK expression has positive correlation with collagen fibers in heart tissue (r=0.938, P<0.01).Meanwhile, the Fn14 expression has positive correlation with TGF-β1 expression in heart tissue (r=0.987, P＜0.01) Conclusions:1. Fn14,TWEAK and TGF-β1 play an important role in inflammation of hypertension;2. Fn14,TWEAK and TGF-β1 highly expressed in heart tissue may aggratate inflammation of hypertension and MF;3. Perindopril may ameliorate myocardial fibrosis through decreasing the expression of Fnl4, TWEAK and TGF-(31 directly or indirectly.
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