Small interfering RNA therapy against carbohydrate sulfotransferase 15 inhibits cardiac remodeling in rats with dilated cardiomyopathy

Watanabe, Kenichi; Arumugam, Somasundaram; Sreedhar, Remya; Thandavarayan, Rajarajan Amirthalingam; Nakamura, Takashi; Nakamura, Masahiko; Harima, Meilei; Yoneyama, Hiroyuki; Suzuki, Kenji

doi:10.1016/j.cellsig.2015.03.004

Cited by 37 publications

(32 citation statements)

References 43 publications

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“…CHST15 is responsible for bone marrow-derived mast cell and pulmonary metastasis 10, 11, 12. The effect of CHST15 siRNA on fibrosis was reported in rats with dilated cardiomyopathy 13 and in murine colitis models 14 . Furthermore, CHST15 siRNA repressed colonic fibrosis and enhanced mucosal healing in patients with Crohn disease, as shown in the safety and efficacy results of a phase 1 study reported by Suzuki et al 15 .…”

Section: Introductionmentioning

confidence: 93%

Silencing of Carbohydrate Sulfotransferase 15 Hinders Murine Pulmonary Fibrosis Development

Kai

Tomoda

Yoneyama

et al. 2017

Molecular Therapy - Nucleic Acids

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Pulmonary fibrosis is a progressive lung disorder characterized by interstitial fibrosis, for which no effective treatments are available. Chondroitin sulfate proteoglycan (CSPG) has been shown to be a mediator, but the specific component of glycosaminoglycan chains of CSPG has not been explored. We show that chondroitin sulfate E-type (CS-E) is involved in fibrogenesis. Small interfering RNA (siRNA) targeting carbohydrate sulfotransferase 15 (CHST15) was designed to inhibit CHST15 mRNA and its product, CS-E. CS-E augments cell contraction and CHST15 siRNA inhibits collagen production. We found that bleomycin treatment increased CHST15 expression in interstitial fibroblasts at day 14. CHST15 siRNA was injected intranasally on days 1, 4, 8, and 11, and CHST15 mRNA was significantly suppressed by day 14. CHST15 siRNA reduced lung CSPG and the grade of fibrosis. CHST15 siRNA repressed the activation of fibroblasts, as evidenced by suppressed expression of α smooth muscle actin (αSMA), connective tissue growth factor (CTGF), lysyl oxidase like 2 (LOXL2), and CC-chemokine ligand 2 (CCL2)/monocyte chemoattractant protein-1 (MCP-1). Inflammatory infiltrates in the bronchoalveolar lavage fluid (BALF) and interstitium were diminished by CHST15 siRNA. These results indicate a pivotal role for CHST15 in fibroblast-mediated lung fibrosis and suggest a possible new therapeutic role for CHST15 siRNA in pulmonary fibrosis.

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Section: Introductionmentioning

confidence: 93%

Silencing of Carbohydrate Sulfotransferase 15 Hinders Murine Pulmonary Fibrosis Development

Kai

Tomoda

Yoneyama

et al. 2017

Molecular Therapy - Nucleic Acids

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“…Most of our current understanding comes from experiments in susceptible murine strains. Human myocarditis is mimicked in mice through infection with human coxsackie virus B3 (CVB3) or by injection of cardiac antigens that induce an autoimmune response . The latter non‐infectious models mainly provide insights into the latter phases of myocarditis.…”

Section: Immune Activation In Different Heart Failure Aetiologiesmentioning

confidence: 99%

The innate immune system in chronic cardiomyopathy: a European Society of Cardiology (ESC) scientific statement from the Working Group on Myocardial Function of the ESC

Frantz

Falcão-Pires

Balligand

et al. 2018

European J of Heart Fail

144

147

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Activation of the immune system in heart failure (HF) has been recognized for over 20 years. Initially, experimental studies demonstrated a maladaptive role of the immune system. However, several phase III trials failed to show beneficial effects in HF with therapies directed against an immune activation. Preclinical studies today describe positive and negative effects of immune activation in HF. These different effects depend on timing and aetiology of HF. Therefore, herein we give a detailed review on immune mechanisms and their importance for the development of HF with a special focus on commonalities and differences between different forms of cardiomyopathies. The role of the immune system in ischaemic, hypertensive, diabetic, toxic, viral, genetic, peripartum, and autoimmune cardiomyopathy is discussed in depth. Overall, initial damage to the heart leads to disease specific activation of the immune system whereas in the chronic phase of HF overlapping mechanisms occur in different aetiologies.

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“…All of these are involved in fibrogenesis and therefore characterize CHST15 and/or CS-E axis as a “fine-tuner” of local fibrosis. We have recently shown that blockade of CHST15 by siRNA repressed cardiac fibrosis in rats with dilated cardiomyopathy through suppressing multiple mediators associated with cardiac remodeling such as interleukin (IL)-1ß, IL-6, monocyte chemoattractant protein (MCP)-1/CCL2, collagen type 1 and 3, MMP-2, MMP-9, connective tissue growth factor (CTGF), TGF-ß and TGF-ß activated kinase (TAK)-1 [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

Pivotal Role of Carbohydrate Sulfotransferase 15 in Fibrosis and Mucosal Healing in Mouse Colitis

et al. 2016

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Induction of mucosal healing (MH) is an important treatment goal in inflammatory bowel disease (IBD). Although the molecular mechanisms underlying MH in IBD is not fully explored, local fibrosis would contribute to interfere mucosal repair. Carbohydrate sulfotransferase 15 (CHST15), which catalyzes sulfation of chondroitin sulfate to produce rare E-disaccharide units, is a novel mediator to create local fibrosis. Here we have used siRNA-based approach of silencing CHST15 in dextran sulfate sodium (DSS) induced colitis in mice, human colon fibroblasts and cancer cell lines. In a DSS-induced acute colitis model, CHST15 siRNA reduced CHST15 mRNA in the colon, serum IL-6, disease activity index (DAI) and accumulation of F4/80+ macrophages and ER-TR7+ fibroblasts, while increased Ki-67+ epithelial cells. In DSS-induced chronic colitis models, CHST15 siRNA reduced CHST15 mRNA in the colon, DAI, alpha-smooth muscle actin+ fibroblasts and collagen deposition, while enhanced MH as evidenced by reduced histological and endoscopic scores. We also found that endoscopic submucosal injection achieved effective pancolonic delivery of CHST15 siRNA in mice. In human CCD-18 Co cells, CHST15 siRNA inhibited the expression of CHST15 mRNA and selectively reduced E-units, a specific product biosynthesized by CHST15, in the culture supernatant. CHST15 siRNA significantly suppressed vimentin in both TGF-ß-stimulated CCD18-Co cells and HCT116 cells while up-regulated BMP7 and E-cadherin in HCT116 cells. The present study demonstrated that blockade CHST15 represses colonic fibrosis and enhances MH partly though reversing EMT pathway, illustrating a novel therapeutic opportunity to refractory and fibrotic lesions in IBD.

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Small interfering RNA therapy against carbohydrate sulfotransferase 15 inhibits cardiac remodeling in rats with dilated cardiomyopathy

Cited by 37 publications

References 43 publications

Silencing of Carbohydrate Sulfotransferase 15 Hinders Murine Pulmonary Fibrosis Development

Silencing of Carbohydrate Sulfotransferase 15 Hinders Murine Pulmonary Fibrosis Development

The innate immune system in chronic cardiomyopathy: a European Society of Cardiology (ESC) scientific statement from the Working Group on Myocardial Function of the ESC

Pivotal Role of Carbohydrate Sulfotransferase 15 in Fibrosis and Mucosal Healing in Mouse Colitis

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