2,5-Dimethylcelecoxib prevents pressure-induced left ventricular remodeling through GSK-3 activation

Ai Fujita, Fumi Takahashi-Yanaga, Sachio Morimoto, Tatsuya Yoshihara, masaki arioka, Kazunobu Igawa, Katsuhiko Tomooka, Sumio Hoka, Toshiyuki Sasaguri

研究成果: ジャーナルへの寄稿記事

7 引用 (Scopus)

抄録

Glycogen synthase kinase-3 (GSK-3) is a crucial regulator of cardiac hypertrophy. We previously reported that 2,5-dimethylcelecoxib (DM-celecoxib), a celecoxib derivative unable to inhibit cyclooxygenase-2, prevented cardiac remodeling by activating GSK-3, resulting in lifespan prolongation in a mouse model of genetic dilated cardiomyopathy. In the present study, we investigated whether DM-celecoxib can also prevent pressure-induced cardiac remodeling and heart failure, elicited by transverse aortic constriction (TAC). Before testing the effects of DM-celecoxib, we compared the effects of TAC on the hearts of wild-type and GSK-3β hetero-deficient (GSK-3β+/-) mice to determine the role of GSK-3 in cardiac remodeling and heart failure. GSK-3β+/- mouse hearts exhibited more severe hypertrophy, which was characterized by accelerated interstitial fibrosis, than wild-type mouse hearts after TAC, suggesting that reduced GSK-3β activity aggravates pressure-induced left ventricular remodeling. We subsequently examined the effects of DM-celecoxib on TAC-induced cardiac remodeling. DM-celecoxib inhibited left ventricular systolic functional deterioration, and prevented left ventricular hypertrophy and fibrosis. It also activated GSK-3α and β by inhibiting Akt, suppressing the activity of β-catenin and nuclear factor of activated T-cells and thereby decreasing the expression of the Wnt/β-catenin target gene products fibronectin and matrix metalloproteinase-2. These results suggest that DM-celecoxib is clinically useful for treating pressure-induced heart diseases.

元の言語英語
ページ(範囲)130-139
ページ数10
ジャーナルHypertension Research
40
発行部数2
DOI
出版物ステータス出版済み - 2 1 2017

Fingerprint

Glycogen Synthase Kinase 3
Ventricular Remodeling
Pressure
Constriction
Heart Failure
Catenins
Celecoxib
Fibrosis
NFATC Transcription Factors
2,5-dimethylcelecoxib
Matrix Metalloproteinase 2
Genetic Models
Dilated Cardiomyopathy
Cardiomegaly
Left Ventricular Hypertrophy
Cyclooxygenase 2
Fibronectins
Hypertrophy
Heart Diseases

All Science Journal Classification (ASJC) codes

  • Internal Medicine
  • Physiology
  • Cardiology and Cardiovascular Medicine

これを引用

2,5-Dimethylcelecoxib prevents pressure-induced left ventricular remodeling through GSK-3 activation. / Fujita, Ai; Takahashi-Yanaga, Fumi; Morimoto, Sachio; Yoshihara, Tatsuya; arioka, masaki; Igawa, Kazunobu; Tomooka, Katsuhiko; Hoka, Sumio; Sasaguri, Toshiyuki.

:: Hypertension Research, 巻 40, 番号 2, 01.02.2017, p. 130-139.

研究成果: ジャーナルへの寄稿記事

@article{a2cf465823c346be8267878e2f960f35,
title = "2,5-Dimethylcelecoxib prevents pressure-induced left ventricular remodeling through GSK-3 activation",
abstract = "Glycogen synthase kinase-3 (GSK-3) is a crucial regulator of cardiac hypertrophy. We previously reported that 2,5-dimethylcelecoxib (DM-celecoxib), a celecoxib derivative unable to inhibit cyclooxygenase-2, prevented cardiac remodeling by activating GSK-3, resulting in lifespan prolongation in a mouse model of genetic dilated cardiomyopathy. In the present study, we investigated whether DM-celecoxib can also prevent pressure-induced cardiac remodeling and heart failure, elicited by transverse aortic constriction (TAC). Before testing the effects of DM-celecoxib, we compared the effects of TAC on the hearts of wild-type and GSK-3β hetero-deficient (GSK-3β+/-) mice to determine the role of GSK-3 in cardiac remodeling and heart failure. GSK-3β+/- mouse hearts exhibited more severe hypertrophy, which was characterized by accelerated interstitial fibrosis, than wild-type mouse hearts after TAC, suggesting that reduced GSK-3β activity aggravates pressure-induced left ventricular remodeling. We subsequently examined the effects of DM-celecoxib on TAC-induced cardiac remodeling. DM-celecoxib inhibited left ventricular systolic functional deterioration, and prevented left ventricular hypertrophy and fibrosis. It also activated GSK-3α and β by inhibiting Akt, suppressing the activity of β-catenin and nuclear factor of activated T-cells and thereby decreasing the expression of the Wnt/β-catenin target gene products fibronectin and matrix metalloproteinase-2. These results suggest that DM-celecoxib is clinically useful for treating pressure-induced heart diseases.",
author = "Ai Fujita and Fumi Takahashi-Yanaga and Sachio Morimoto and Tatsuya Yoshihara and masaki arioka and Kazunobu Igawa and Katsuhiko Tomooka and Sumio Hoka and Toshiyuki Sasaguri",
year = "2017",
month = "2",
day = "1",
doi = "10.1038/hr.2016.122",
language = "English",
volume = "40",
pages = "130--139",
journal = "Hypertension Research",
issn = "0916-9636",
publisher = "Nature Publishing Group",
number = "2",

}

TY - JOUR

T1 - 2,5-Dimethylcelecoxib prevents pressure-induced left ventricular remodeling through GSK-3 activation

AU - Fujita, Ai

AU - Takahashi-Yanaga, Fumi

AU - Morimoto, Sachio

AU - Yoshihara, Tatsuya

AU - arioka, masaki

AU - Igawa, Kazunobu

AU - Tomooka, Katsuhiko

AU - Hoka, Sumio

AU - Sasaguri, Toshiyuki

PY - 2017/2/1

Y1 - 2017/2/1

N2 - Glycogen synthase kinase-3 (GSK-3) is a crucial regulator of cardiac hypertrophy. We previously reported that 2,5-dimethylcelecoxib (DM-celecoxib), a celecoxib derivative unable to inhibit cyclooxygenase-2, prevented cardiac remodeling by activating GSK-3, resulting in lifespan prolongation in a mouse model of genetic dilated cardiomyopathy. In the present study, we investigated whether DM-celecoxib can also prevent pressure-induced cardiac remodeling and heart failure, elicited by transverse aortic constriction (TAC). Before testing the effects of DM-celecoxib, we compared the effects of TAC on the hearts of wild-type and GSK-3β hetero-deficient (GSK-3β+/-) mice to determine the role of GSK-3 in cardiac remodeling and heart failure. GSK-3β+/- mouse hearts exhibited more severe hypertrophy, which was characterized by accelerated interstitial fibrosis, than wild-type mouse hearts after TAC, suggesting that reduced GSK-3β activity aggravates pressure-induced left ventricular remodeling. We subsequently examined the effects of DM-celecoxib on TAC-induced cardiac remodeling. DM-celecoxib inhibited left ventricular systolic functional deterioration, and prevented left ventricular hypertrophy and fibrosis. It also activated GSK-3α and β by inhibiting Akt, suppressing the activity of β-catenin and nuclear factor of activated T-cells and thereby decreasing the expression of the Wnt/β-catenin target gene products fibronectin and matrix metalloproteinase-2. These results suggest that DM-celecoxib is clinically useful for treating pressure-induced heart diseases.

AB - Glycogen synthase kinase-3 (GSK-3) is a crucial regulator of cardiac hypertrophy. We previously reported that 2,5-dimethylcelecoxib (DM-celecoxib), a celecoxib derivative unable to inhibit cyclooxygenase-2, prevented cardiac remodeling by activating GSK-3, resulting in lifespan prolongation in a mouse model of genetic dilated cardiomyopathy. In the present study, we investigated whether DM-celecoxib can also prevent pressure-induced cardiac remodeling and heart failure, elicited by transverse aortic constriction (TAC). Before testing the effects of DM-celecoxib, we compared the effects of TAC on the hearts of wild-type and GSK-3β hetero-deficient (GSK-3β+/-) mice to determine the role of GSK-3 in cardiac remodeling and heart failure. GSK-3β+/- mouse hearts exhibited more severe hypertrophy, which was characterized by accelerated interstitial fibrosis, than wild-type mouse hearts after TAC, suggesting that reduced GSK-3β activity aggravates pressure-induced left ventricular remodeling. We subsequently examined the effects of DM-celecoxib on TAC-induced cardiac remodeling. DM-celecoxib inhibited left ventricular systolic functional deterioration, and prevented left ventricular hypertrophy and fibrosis. It also activated GSK-3α and β by inhibiting Akt, suppressing the activity of β-catenin and nuclear factor of activated T-cells and thereby decreasing the expression of the Wnt/β-catenin target gene products fibronectin and matrix metalloproteinase-2. These results suggest that DM-celecoxib is clinically useful for treating pressure-induced heart diseases.

UR - http://www.scopus.com/inward/record.url?scp=85011653940&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85011653940&partnerID=8YFLogxK

U2 - 10.1038/hr.2016.122

DO - 10.1038/hr.2016.122

M3 - Article

VL - 40

SP - 130

EP - 139

JO - Hypertension Research

JF - Hypertension Research

SN - 0916-9636

IS - 2

ER -