TY - JOUR
T1 - Small interfering RNA therapy against carbohydrate sulfotransferase 15 inhibits cardiac remodeling in rats with dilated cardiomyopathy
AU - Watanabe, Kenichi
AU - Arumugam, Somasundaram
AU - Sreedhar, Remya
AU - Thandavarayan, Rajarajan A.
AU - Nakamura, Takashi
AU - Nakamura, Masahiko
AU - Harima, Meilei
AU - Yoneyama, Hiroyuki
AU - Suzuki, Kenji
N1 - Funding Information:
This research was supported by a Yujin Memorial Grant, Ministry of Education, Culture, Sports, Science, and Technology, Japan ( 23602012 ), and by a grant from the promotion and Mutual Aid Corporation for Private Schools, Japan ( 26460239 ), and by Japan Science and Technology Agency (JST, AS2117901G ), Japan. We thank Wawaimuli Arozal, Flori Ratna Sari, Hiroko Shimazaki, Sayaka Egawa, Fuji Tomohiko, Kana Kawadura, Yoshiyasu Kobayashi, and Yuhki for their assistance in this research work. We also express our sincere gratitude to Dr. Masaki Nagata (Division of Oral and Maxillofacial Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan) for carrying out RT-PCR analysis to this study.
Publisher Copyright:
© 2015 Elsevier Inc.
PY - 2015/7/1
Y1 - 2015/7/1
N2 - Carbohydrate sulfotransferase 15 (CHST15) is a sulfotransferase responsible for biosynthesis of chondroitin sulfate E (CS-E), which plays important roles in numerous biological events such as biosynthesis of proinflammatory cytokines. However, the effects of CHST15 siRNA in rats with chronic heart failure (CHF) after experimental autoimmune myocarditis (EAM) have not yet been investigated. CHF was elicited in Lewis rats by immunization with cardiac myosin, and after immunization, the rats were divided into two groups and treated with either CHST15 siRNA (2. μg/week) or vehicle. Age matched normal rats without immunizations were also included in this study. After 7. weeks of treatment, we investigated the effects of CHST15 siRNA on cardiac function, proinflammatory cytokines, and cardiac remodeling in EAM rats. Myocardial functional parameters measured by hemodynamic and echocardiographic studies were significantly improved by CHST15 siRNA treatment in rats with CHF compared with that of vehicle-treated CHF rats. CHST15 siRNA significantly reduced cardiac fibrosis, and hypertrophy and its marker molecules (left ventricular (LV) mRNA expressions of transforming growth factor beta1, collagens I and III, and atrial natriuretic peptide) compared with vehicle-treated CHF rats. CHF-induced increased myocardial mRNA expressions of proinflammatory cytokines [interleukin (IL)-6, IL-1β], monocyte chemoattractant protein-1, and matrix metalloproteinases (MMP-2 and -9), and CHST15 were also suppressed by the treatment with CHST15 siRNA. Western blotting study has confirmed the results obtained from mRNA analysis as CHST15 siRNA treated rats expressed reduced levels of inflammatory and cardiac remodeling marker proteins. Our results demonstrate for the first time, that CHST15 siRNA treatment significantly improved LV function and ameliorated the progression of cardiac remodeling in rats with CHF after EAM.
AB - Carbohydrate sulfotransferase 15 (CHST15) is a sulfotransferase responsible for biosynthesis of chondroitin sulfate E (CS-E), which plays important roles in numerous biological events such as biosynthesis of proinflammatory cytokines. However, the effects of CHST15 siRNA in rats with chronic heart failure (CHF) after experimental autoimmune myocarditis (EAM) have not yet been investigated. CHF was elicited in Lewis rats by immunization with cardiac myosin, and after immunization, the rats were divided into two groups and treated with either CHST15 siRNA (2. μg/week) or vehicle. Age matched normal rats without immunizations were also included in this study. After 7. weeks of treatment, we investigated the effects of CHST15 siRNA on cardiac function, proinflammatory cytokines, and cardiac remodeling in EAM rats. Myocardial functional parameters measured by hemodynamic and echocardiographic studies were significantly improved by CHST15 siRNA treatment in rats with CHF compared with that of vehicle-treated CHF rats. CHST15 siRNA significantly reduced cardiac fibrosis, and hypertrophy and its marker molecules (left ventricular (LV) mRNA expressions of transforming growth factor beta1, collagens I and III, and atrial natriuretic peptide) compared with vehicle-treated CHF rats. CHF-induced increased myocardial mRNA expressions of proinflammatory cytokines [interleukin (IL)-6, IL-1β], monocyte chemoattractant protein-1, and matrix metalloproteinases (MMP-2 and -9), and CHST15 were also suppressed by the treatment with CHST15 siRNA. Western blotting study has confirmed the results obtained from mRNA analysis as CHST15 siRNA treated rats expressed reduced levels of inflammatory and cardiac remodeling marker proteins. Our results demonstrate for the first time, that CHST15 siRNA treatment significantly improved LV function and ameliorated the progression of cardiac remodeling in rats with CHF after EAM.
KW - CHST15 siRNA
KW - Cardiac remodeling
KW - Chronic heart failure
KW - Experimental autoimmune myocarditis
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U2 - 10.1016/j.cellsig.2015.03.004
DO - 10.1016/j.cellsig.2015.03.004
M3 - Article
C2 - 25778904
AN - SCOPUS:84939941312
SN - 0898-6568
VL - 27
SP - 1517
EP - 1524
JO - Cellular Signalling
JF - Cellular Signalling
IS - 7
ER -