ABSTRACT
OBJECTIVE: Myocardial infarction (MI) is one of the most common diseases in cardiovascular medicine, and the risk of MI is very serious. Therefore, the purpose of this study was to explore the effect of fasudil on isoproterenol (ISO)-induced MI in mice. MATERIALS AND METHODS: Forty C57BL/6 mice were divided into four groups, namely, control group, MI group, low dose fasudil and MI treatment group (low fasudil group), high dose fasudil, and MI treatment Group (high fasudil group). MI group and the fasudil group were injected subcutaneously with ISO (85 mg/kg) twice, and every 24 h MI was induced. Low-dose and high-dose fasudil groups were treated with 3 mg/kg/day and 10 mg/kg/day for 4 weeks before the injection of ISO. Cardiac function measured in the fourth week after ISO injection, and body weight and whole heart weight were weighed. Infarct area and thickness were analyzed by HE staining. Besides, the degree of myocardial damage was measured by detecting serum CK and LDH, and excised heart tissue was detected by Real Time-Polymerase Chain Reaction (PCR) and Western blot. RESULTS: In MI group, the cardiac function was significantly decreased: the left ventricular short axis shortening rate (FS) and left ventricular ejection fraction (EF) were significantly decreased, the left ventricular volume was significantly increased, and the myocardial injury markers CK and LDH were significantly increased. In addition, fasudil treatment significantly relieved heart function after MI in a dose-dependent manner, reducing cardiomyocytes oxidative damage, inhibiting apoptosis. CONCLUSIONS: Fasudil can reduce ISO-induced MI, reducing cardiomyocytes oxidative damage, inhibiting apoptosis by inhibiting the Rho/ROCK signaling pathway.
Subject(s)
1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine/analogs & derivatives , Myocardial Infarction/drug therapy , Protective Agents/pharmacology , Protein Kinase Inhibitors/pharmacology , rho-Associated Kinases/antagonists & inhibitors , rhoC GTP-Binding Protein/antagonists & inhibitors , 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine/administration & dosage , 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine/pharmacology , Animals , Dose-Response Relationship, Drug , Injections, Subcutaneous , Isoproterenol/antagonists & inhibitors , Mice , Mice, Inbred C57BL , Myocardial Infarction/chemically induced , Oxidative Stress/drug effects , Protective Agents/administration & dosage , Protein Kinase Inhibitors/administration & dosage , Signal Transduction/drug effects , rho-Associated Kinases/metabolism , rhoC GTP-Binding Protein/metabolismABSTRACT
The stromal reaction in pancreatic cancer creates a physical barrier that blocks therapeutic intervention and creates an immunosuppressive tumor microenvironment. The Rho/myocardin-related transcription factor (MRTF) pathway is implicated in the hyper-activation of fibroblasts in fibrotic diseases and the activation of pancreatic stellate cells. In this study we use CCG-222740, a small molecule, designed as a Rho/MRTF pathway inhibitor. This compound decreases the activation of stellate cells in vitro and in vivo, by reducing the levels of alpha smooth muscle actin (α-SMA) expression. CCG-222740 also modulates inflammatory components of the pancreas in KC mice (LSL-KrasG12D/+; Pdx-1-Cre) stimulated with caerulein. It decreases the infiltration of macrophages and increases CD4 T cells and B cells. Analysis of the pancreatic adenocarcinoma (PDA) TCGA dataset revealed a correlation between elevated RhoA, RhoC and MRTF expression and decreased survival in PDA patients. Moreover, a MRTF signature is correlated with a Th2 cell signature in human PDA tumors.
Subject(s)
Adenocarcinoma/metabolism , Pancreatic Neoplasms/metabolism , Pancreatic Stellate Cells/drug effects , Trans-Activators/antagonists & inhibitors , Transcription Factors/antagonists & inhibitors , rhoA GTP-Binding Protein/antagonists & inhibitors , rhoC GTP-Binding Protein/antagonists & inhibitors , Animals , Disease Models, Animal , Female , Gene Knock-In Techniques , Homeodomain Proteins/genetics , Integrases/genetics , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Pancreatic Stellate Cells/metabolism , Proto-Oncogene Proteins p21(ras)/genetics , RAW 264.7 Cells , Trans-Activators/genetics , Trans-Activators/metabolism , Transcription Factors/metabolism , rhoA GTP-Binding Protein/metabolism , rhoC GTP-Binding Protein/metabolismABSTRACT
Previous studies have shown that 4.1 proteins, which are deregulated in many cancers, contribute to cell adhesion and motility. Yurt/Mosaic eyes-like 1 (YMO1) is a member of 4.1 protein family but it is unclear whether YMO1 plays a role in tumor invasion. This study aimed to investigate the effects of YMO1 on hepatocellular carcinoma (HCC) and attempted to elucidate the underlying molecular mechanisms. YMO1 expression in HCC tissues and its correlation with clinicopathological features and postoperative prognosis was analyzed. The results showed that YMO1 was down-regulated in the highly metastatic HCC cell line and in human tumor tissues. Underexpression of YMO1 indicated poor prognosis of HCC patients. Restoration of YMO1 expression caused a significant decrease in cell migration and invasiveness in vitro. In vivo study showed that YMO1 reduced liver tumor invasion and metastasis in xenograft mice. YMO1 directly inhibited RhoC activation. YMO1 expression in HCC was regulated by PAX5. Analysis of YMO1 expression levels in human HCC patients revealed a significant correlation of YMO1 expression with PAX5 and RhoC. Our findings revealed that YMO1 predicts favorable prognosis and the data suggest that YMO1 suppresses tumor invasion and metastasis by inhibiting RhoC activity.
