Abstract 297: Development of Molecular Targeted Therapy Against Right Ventricular Failure: Involvement in a Network of Immunocompetent Cells

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Shogo Ito ◽  
Shinsuke Yuasa ◽  
Jin Komuro ◽  
Mai Kimura ◽  
Dai Kusumoto ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ventricular Arrhythmia ◽  
Right Ventricular ◽  
Microarray Analysis ◽  
Pathway Analysis ◽  
Therapeutic Target ◽  
Immunocompetent Cells ◽  
Wild Type ◽  
Novel Therapeutic

Backgrounds: Right ventricular (RV) failure plays a critical role in right heart failure and left heart failure. However, there is no specific therapy developed for RV failure. To elucidate a novel therapeutic target against RV failure, we focus on RV specific genes to develop novel therapeutics for RV failure. Methods: Microarray analysis using several parts of adult murine heart was conducted and differentially expressed genes (DEGs) were applied to pathway analysis. Molecular mechanism was examined by using neonatal rat ventricular cardiomyocyte (NRVM) in vitro. To understand the function of target molecule in vivo, we induced RV failure by pulmonary artery constriction (PAC) in mice and inhibition experiments were performed using RV failure model. Results: In microarray analysis for RV, left ventricle and ventricular septum, 995 genes were extracted as DEGs in RV. Pathway analysis showed that alternative complement pathway-related genes were significantly up-regulated in RV. Moreover, complement factor D (Cfd) and C3a was a potential upstream factor attributable to unique feature of RV. Administration of C3a recombinant protein to NRVM phosphorylated several MAP kinases. In vivo, in C3KO PAC mice, RV dysfunction was significantly suppressed, and histological study showed that RV fibrosis was significantly suppressed. In wild type mice with PAC, administration of C3a receptor antagonist dramatically improved RV dysfunction and reduced RV fibrosis. Additionally, in vivo electrophysiological study revealed that the inducibility of ventricular arrhythmia was increased in wild type PAC mice, but ventricular arrhythmia was significantly attenuated in C3KO PAC mice. Furthermore, the expression of chemokine Ccl5 was enhanced in RV of wild type PAC mice, while Ccl5 was significantly attenuated in C3KO PAC mice. Conclusion: We revealed that complement C3a was highly produced in RV and chemical or genetical blockade of C3a ameliorates RV dysfunction and RV fibrosis in PAC mice. C3a was to be a potent bioactive protein for immunocompetent cells that played an important role in modulating cardiac function. Accordingly, we demonstrated that the blockade of C3a had a potential role for novel therapeutic target to RV failure.

Abstract 12947: Development of Molecular Targeted Therapy Against Right Ventricular Failure: Involvement in A Network of Immunocompetent Cells

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Shogo Ito ◽  
Shinsuke Yuasa ◽  
Jin Komuro ◽  
Mai Kimura ◽  
Dai Kusumoto ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ventricular Arrhythmia ◽  
Right Ventricular ◽  
Differentially Expressed Genes ◽  
Pathway Analysis ◽  
Therapeutic Target ◽  
Failure Model ◽  
Wild Type ◽  
Novel Therapeutic

Backgrounds: Right ventricular (RV) failure plays a critical role in right heart failure and left heart failure. However, there is no specific therapy developed for RV failure. To elucidate a novel therapeutic target against RV failure, we focus on differentially expressed genes in RV to develop novel therapeutics for RV failure. Methods: Microarray analysis using several parts of adult murine heart was conducted and differentially expressed genes (DEGs) were applied to pathway analysis by Ingenuity Pathway Analysis R . Molecular mechanism was examined by using neonatal rat ventricular cardiomyocyte (NRVM) in vitro . To understand the function of target molecule in vivo , we induced RV failure by pulmonary artery constriction (PAC) in mice and inhibition experiments were performed using these RV failure model mice. Results: In microarray analysis for RV, left ventricle and ventricular septum, 995 genes were extracted as DEGs in RV. Pathway analysis revealed that alternative complement pathway-related genes were significantly up-regulated in RV. Moreover, complement factor D (Cfd) and C3a was a potential upstream factor attributable to unique feature of RV. Administration of C3a recombinant protein to NRVM phosphorylated several MAP kinases. Moreover, in C3KO PAC mice, RV dysfunction was significantly suppressed, and histological study suggested that RV fibrosis was significantly suppressed by comparing to wild type PAC mice. Furthermore, administration of C3a receptor antagonist to wild type PAC mice dramatically improved RV dysfunction and reduced RV fibrosis. Additionally, in vivo electrophysiological study revealed that the inducibility of ventricular arrhythmia was increased in wild type PAC mice, but ventricular arrhythmia was significantly attenuated in C3KO PAC mice. Conclusion: We revealed that complement C3a was highly produced in RV, and genetic or chemical blockade of C3a ameliorates RV dysfunction and RV fibrosis in RV failure model mice. C3a was to be a potent bioactive protein for immunocompetent cells that played an important role in modulating RV function. Accordingly, we demonstrated that the blockade of C3a had a potential role for novel therapeutic target of RV failure.

scholarly journals Carcinoembryonic antigen cell adhesion molecule 6 (CEACAM6) in Pancreatic Ductal Adenocarcinoma (PDA): An integrative analysis of a novel therapeutic target

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Ritu Pandey ◽  
Muhan Zhou ◽  
Shariful Islam ◽  
Baowei Chen ◽  
Natalie K Barker ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Therapeutic Target ◽  
Cell Activity ◽  
Gene Expression Omnibus ◽  
The Cancer Genome Atlas ◽  
Ductal Adenocarcinoma ◽  
Wild Type ◽  
Cancer Genome Atlas ◽  
Novel Therapeutic

AbstractWe investigated biomarker CEACAM6, a highly abundant cell surface adhesion receptor that modulates the extracellular matrix (ECM) in pancreatic ductal adenocarcinoma (PDA). The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) RNA-Seq data from PDA patients were analyzed for CEACAM6 expression and evaluated for overall survival, association, enrichment and correlations. A CRISPR/Cas9 Knockout (KO) of CEACAM6 in PDA cell line for quantitative proteomics, mitochondrial bioenergetics and tumor growth in mice were conducted. We found CEACAM6 is over-expressed in primary and metastatic basal and classical PDA subtypes. Highest levels are in classical activated stroma subtype. CEACAM6 over-expression is universally a poor prognostic marker in KRAS mutant and wild type PDA. High CEACAM6 expression is associated with low cytolytic T-cell activity in both basal and classical PDA subtypes and correlates with low levels of T-REG markers. In HPAF-II cells knockout of CEACAM6 alters ECM-cell adhesion, catabolism, immune environment, transmembrane transport and autophagy. CEACAM6 loss increases mitochondrial basal and maximal respiratory capacity. HPAF-II CEACAM6−/− cells are growth suppressed by >65% vs. wild type in mice bearing tumors. CEACAM6, a key regulator affects several hallmarks of PDA including the fibrotic reaction, immune regulation, energy metabolism and is a novel therapeutic target in PDA.

scholarly journals CBP/β-Catenin/FOXM1 Is a Novel Therapeutic Target in Triple Negative Breast Cancer

Cancers ◽  
2018 ◽  
Vol 10 (12) ◽  
pp. 525 ◽  
Author(s):  
Alexander Ring ◽  
Cu Nguyen ◽  
Goar Smbatyan ◽  
Debu Tripathy ◽  
Min Yu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Drug Resistance ◽  
Triple Negative Breast Cancer ◽  
Therapeutic Target ◽  
Triple Negative ◽  
Creb Binding Protein ◽  
Novel Therapeutic

Background: Triple negative breast cancers (TNBCs) are an aggressive BC subtype, characterized by high rates of drug resistance and a high proportion of cancer stem cells (CSC). CSCs are thought to be responsible for tumor initiation and drug resistance. cAMP-response element-binding (CREB) binding protein (CREBBP or CBP) has been implicated in CSC biology and may provide a novel therapeutic target in TNBC. Methods: RNA Seq pre- and post treatment with the CBP-binding small molecule ICG-001 was used to characterize CBP-driven gene expression in TNBC cells. In vitro and in vivo TNBC models were used to determine the therapeutic effect of CBP inhibition via ICG-001. Tissue microarrays (TMAs) were used to investigate the potential of CBP and associated proteins as biomarkers in TNBC. Results: The CBP/ß-catenin/FOXM1 transcriptional complex drives gene expression in TNBC and is associated with increased CSC numbers, drug resistance and poor survival outcome. Targeting of CBP/β-catenin/FOXM1 with ICG-001 eliminated CSCs and sensitized TNBC tumors to chemotherapy. Immunohistochemistry of TMAs demonstrated a significant correlation between FOXM1 expression and TNBC subtype. Conclusion: CBP/β-catenin/FOXM1 transcriptional activity plays an important role in TNBC drug resistance and CSC phenotype. CBP/β-catenin/FOXM1 provides a molecular target for precision therapy in triple negative breast cancer and could form a rationale for potential clinical trials.

Abstract 533: Crucial Role of Rho-Kinase in Pressure Overload--Induced Right Ventricular Hypertrophy and Dysfunction in Mice: A Possible Novel Therapeutic Target of Right Ventricular Failure

2014 ◽  
Vol 34 (suppl_1) ◽  
Author(s):  
Shohei Ikeda ◽  
Kimio Satoh ◽  
Nobuhiro Kikuchi ◽  
Satoshi Miyata ◽  
Kota Suzuki ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Right Ventricular ◽  
Therapeutic Target ◽  
Crucial Role ◽  
Molecular Mechanisms ◽  
Rho Kinase ◽  
Pressure Overload ◽  
Dominant Negative ◽  
Term Survival ◽  
Novel Therapeutic

Rationale: Right ventricular (RV) failure is the leading cause of death in various cardiopulmonary diseases, including pulmonary hypertension. It is generally considered that the RV is vulnerable to pressure-overload as compared with the left ventricle (LV). However, as compared with LV failure, the molecular mechanisms of RV failure are poorly understood. Objective: We aimed to identify molecular therapeutic targets for RV failure in a mouse model of pressure-overload. Methods and Results: To induce pressure-overload to respective ventricles, we performed pulmonary artery constriction (PAC) or transverse aortic constriction (TAC) in mice. We first performed microarray analysis and found that the molecules related to RhoA/Rho-kinase and integrin pathways were significantly up-regulated in the RV with PAC compared with the LV with TAC. Then, we examined the responses of both ventricles to chronic pressure-overload in vivo. We demonstrated that compared with TAC, PAC caused greater extents of mortality, Rho-kinase expression (especially ROCK2 isoform) and oxidative stress in pressure-overloaded RV, reflecting the weakness of the RV in response to pressure-overload. Additionally, mechanical stretch of RV cardiomyocytes from rats immediately up-regulated ROCK2 expression (not ROCK1), suggesting the specific importance of ROCK2 in stretch-induced responses of RV tissues. Furthermore, mice with myocardial-specific overexpression of dominant-negative Rho-kinase (DN-RhoK) showed resistance to pressure-overload-induced hypertrophy and dysfunction associated with reduced oxidative stress. Finally, DN-RhoK mice showed a significantly improved long-term survival in both PAC and TAC as compared with littermate controls. Conclusions: These results indicate that the Rho-kinase pathway plays a crucial role in RV hypertrophy and dysfunction, suggesting that the pathway is a novel therapeutic target of RV failure in humans.

Sign in / Sign up

Export Citation Format

Share Document