Cardiac fibrosis: Histological features, molecular pathways and therapeutic targets

Cardiac fibrosis is defined as the unbalanced production and degradation of cardiac interstitial extracellular matrix(ECM),leading to systolic and diastolic dysfunction,arrhythmias,and adverse outcomes of many cardiac pathophysiological conditions.The accumulation of myocardial ECM increases the risk of arrhythmias and impairs cardiac function,ultimately leading to the development of heart failure.Although slowing or reversing the development of excessive accumulation of ECM and cardiac fibrosis is important for maintaining cardiac function,there is currently no approved treatment for them.Activated cardiac fibroblasts are the main effector cells of cardiac fibrosis.Their expansion after pathophysiologic stimuli such as pressure overload,volume overload,metabolic dysfunction,wound healing,and aging is primarily driven by activating resident interstitial populations.While cardiac fibroblasts are the primary effector cells in the fibrotic heart,monocytes/macrophages,lymphocytes,mast cells,vascular cells,and cardiomyocytes may also contribute to the fibrotic response,by secreting critical fibrotic factors and matricellular proteins.This review discusses histological features,molecular pathways involved in the pathogenesis of cardiac fibrosis and possible therapeutic targets.Understanding the occurrence,development and diffusion mechanisms of cardiac fibrosis has important clinical implications for the discovery of drugs to prevent the progression of cardiac fibrosis.

Reduced expression of E-cadherin/catenin complex in hepatocellular carcinomas

AIM： TO examine the immunoreactivity of E-cadherin and four subtypes of catenin family in human hepatocellular carcinomas （HCCs） and to investigate the correlation between expression of E-cadherin/ catenin complex and clinicopathologic parameters of HCC patients. METHODS： An immunohistochemical study for E-cadherin and catenins was performed on 97 formalin-fixed, paraffin-embedded specimens of HCC. RESULTS： Reduced expression of E-cadherin, ^-, 13-, y-catenin and p120 was observed in 69%, 76%, 63%, 71% and 73%, respectively. Both expressions of E-cadherin and catenin components were significantly correlated with tumor grade （P = 0.000）. It showed significant difference between expression of catenin members and tumor stage （P = 0.003, P = 0.017, P = 0.007 and P = 0.000, respectively）. The reduced expression of E-cadherin in HCCs was significantly correlated with intrahepatic metastasis （IM） and capsular invasion （P = 0.008, P = 0.03, respectively）. A close correlation was also observed between the expression of catenins and the tumor size （P = 0.002, P = 0.034, P = 0.016 and P = 0.000, respectively）. In addition, the expression of each catenin was found correlated with IM （P = 0.012, P = 0.049, P =0.026 and P = 0.014, respectively）. No statistically significant difference was observed between the expression level of E-cadherin/catenin complex and lymph node permission, vascular invasion and satellite nodules. Interestingly, only expression of p120 showed correlation with AFP value （P = 0.035）. The expression of E-cadherin was consistent with α-, β-, γ-catenin and p120 expression （P = 0.000）. Finally, the abnormal expression of E-cadherin/catenin complex was significantly associated with patients＇ survival （P = 0.0253, P = 0.0052, P = 0.003, P = 0.0105 and P = 0.0016, respectively）. Nevertheless, no component of E-cadherin/catenin complex was the independent prognostic factor of HCC patients. CONCLUSION： Down-regulated expressions of E-cadherin, catenins and p120 occur frequently in HCCs and contribute to the progression and development of tumor. It may be more exact and valuable to detect the co-expression of E-cadherin/catenin complex than to explore one of them in predicting tumor invasion, metastasis and patient＇s survival.