The prostaglandin agonist beraprost aggravates doxorubicin-mediated apoptosis by increasing iNOS expression in cardiomyocytes

Wei Shiung Lian, Herng Cheng Chiou, Heng Lin, Jin Jer Chen, Ching Feng Cheng

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Doxorubicin (DOX) is widely used as an anti-cancer agent although it causes irreversible cardiomyopathy by increasing oxidative stress and deregulating nitric oxide production. Beraprost (BPS), a stable prostacyclin (PGI2) analog, is a potent vasodilator that has beneficial effects on myocardial ischemia. The objectives of the present study were to delineate the uncertain effects of prostcyclin therapy on DOX induced cardiomyopathy and to explore the mechanisms underlying PGI2 and DOX interaction. For this reason, we stimulated endogenous PGI2 production using bicistronic COX-1/PGIS gene transfer and BPS supplementation, and investigated the effects on DOX-induced cardiomyopathy. Caspase-dependent protein content, lactate dehydrogenase (LDH), DNA fragmentation, and TUNEL positive cells were elevated in DOX-treated cardiomyocytes. These indicators were further elevated by adenovirus-COX- 1/PGIS transfection or BPS supplementation. In addition, PGI2 overexpression further increased iNOS expression and superoxide accumulation in cardiomyocytes compared with DOX alone, which may be the reason for aggravated cytotoxicity. Moreover, BPS can induce cAMP response elements (CRE) binding to the iNOS promoter and phospho- cAMP response element binding protein (CREB) expression in a cyclic AMP-dependent manner. Our in vivo studies show that MnTBAP and aminoguanidine treatment of DOX and BPS co-administered in mice can attenuate caspase-3 and PARP-1 protein expression, and improve mouse survival, as observed in the iNOS gene-deleted mice. In conclusion, we demonstrated that BPS or adv-COX-1/PGIS increases PGI2 levels through iNOS expression and peroxynitrite production, via CREB protein phosphorylation; thereby aggravating DOX-mediated cardiotoxicity.

Original languageEnglish
Pages (from-to)54-63
Number of pages10
JournalCurrent Vascular Pharmacology
Volume13
Issue number1
Publication statusPublished - 2015

Fingerprint

beraprost
Cardiac Myocytes
Doxorubicin
Prostaglandins
Epoprostenol
Apoptosis
Cardiomyopathies
Cyclic AMP Response Element-Binding Protein
Peroxynitrous Acid
In Situ Nick-End Labeling
Response Elements
DNA Fragmentation
Caspases
Vasodilator Agents
L-Lactate Dehydrogenase

Keywords

  • Beraprost
  • cAMP response element binding protein (CREB)
  • Cardiomyocytes
  • Doxorubicin
  • Inducible nitric oxide synthase (iNOS)
  • Prostacyclin (PGI<inf>2</inf>)

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Pharmacology

Cite this

The prostaglandin agonist beraprost aggravates doxorubicin-mediated apoptosis by increasing iNOS expression in cardiomyocytes. / Lian, Wei Shiung; Chiou, Herng Cheng; Lin, Heng; Chen, Jin Jer; Cheng, Ching Feng.

In: Current Vascular Pharmacology, Vol. 13, No. 1, 2015, p. 54-63.

Research output: Contribution to journalArticle

Lian, Wei Shiung ; Chiou, Herng Cheng ; Lin, Heng ; Chen, Jin Jer ; Cheng, Ching Feng. / The prostaglandin agonist beraprost aggravates doxorubicin-mediated apoptosis by increasing iNOS expression in cardiomyocytes. In: Current Vascular Pharmacology. 2015 ; Vol. 13, No. 1. pp. 54-63.
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AB - Doxorubicin (DOX) is widely used as an anti-cancer agent although it causes irreversible cardiomyopathy by increasing oxidative stress and deregulating nitric oxide production. Beraprost (BPS), a stable prostacyclin (PGI2) analog, is a potent vasodilator that has beneficial effects on myocardial ischemia. The objectives of the present study were to delineate the uncertain effects of prostcyclin therapy on DOX induced cardiomyopathy and to explore the mechanisms underlying PGI2 and DOX interaction. For this reason, we stimulated endogenous PGI2 production using bicistronic COX-1/PGIS gene transfer and BPS supplementation, and investigated the effects on DOX-induced cardiomyopathy. Caspase-dependent protein content, lactate dehydrogenase (LDH), DNA fragmentation, and TUNEL positive cells were elevated in DOX-treated cardiomyocytes. These indicators were further elevated by adenovirus-COX- 1/PGIS transfection or BPS supplementation. In addition, PGI2 overexpression further increased iNOS expression and superoxide accumulation in cardiomyocytes compared with DOX alone, which may be the reason for aggravated cytotoxicity. Moreover, BPS can induce cAMP response elements (CRE) binding to the iNOS promoter and phospho- cAMP response element binding protein (CREB) expression in a cyclic AMP-dependent manner. Our in vivo studies show that MnTBAP and aminoguanidine treatment of DOX and BPS co-administered in mice can attenuate caspase-3 and PARP-1 protein expression, and improve mouse survival, as observed in the iNOS gene-deleted mice. In conclusion, we demonstrated that BPS or adv-COX-1/PGIS increases PGI2 levels through iNOS expression and peroxynitrite production, via CREB protein phosphorylation; thereby aggravating DOX-mediated cardiotoxicity.

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