N-Acetylcysteine and allopurinol up-regulated the Jak/STAT3 and PI3K/Akt pathways via adiponectin and attenuated myocardial postischemic injury in diabetes

Tingting Wang, Xiaowen Mao, Haobo Li, Shigang Qiao, Aimin Xu, Junwen Wang, Shaoqing Lei, Zipeng Liu, Kwok F J Ng, Gordon T. Wong, Paul M. Vanhoutte, Michael G. Irwin, Zhengyuan Xia

Research output: Contribution to journalArticle

60 Citations (Scopus)

Abstract

N-Acetylcysteine (NAC) and allopurinol (ALP) synergistically reduce myocardial ischemia reperfusion (MI/R) injury in diabetes. However, the mechanism is unclear. We postulated that NAC and ALP attenuated diabetic MI/R injury by up-regulating phosphatidylinositol 3-kinase/Akt (PI3K/Akt) and Janus kinase 2/signal transducer and activator of transcription-3 (JAK2/STAT3) pathways subsequent to adiponectin (APN) activation. Control (C) or streptozotocin-induced diabetic rats (D) were untreated or treated with NAC and ALP followed by MI/R. D rats displayed larger infarct size accompanied by decreased phosphorylation of Akt, STAT3 and decreased cardiac nitric oxide (NO) and APN levels. NAC and ALP decreased MI/R injury in D rats, enhanced phosphorylation of Akt and STAT3, and increased NO and APN. High glucose and hypoxia/reoxygenation exposure induced cell death and Akt and STAT3 inactivation in cultured cardiomyocytes, which were prevented by NAC and ALP. The PI3K inhibitor wortmannin and Jak2 inhibitor AG490 abolished the protection of NAC and ALP. Similarly, APN restored posthypoxic Akt and STAT3 activation and decreased cell death in cardiomyocytes. Gene silencing with AdipoR2 siRNA or STAT3 siRNA but not AdipoR1 siRNA abolished the protection of NAC and ALP. In conclusion, NAC and ALP prevented diabetic MI/R injury through PI3K/Akt and Jak2/STAT3 and cardiac APN may serve as a mediator via AdipoR2 in this process.

Original languageEnglish (US)
Pages (from-to)291-303
Number of pages13
JournalFree Radical Biology and Medicine
Volume63
DOIs
StatePublished - 2013
Externally publishedYes

Fingerprint

Phosphatidylinositol 3-Kinase
Allopurinol
Adiponectin
Acetylcysteine
Medical problems
Myocardial Reperfusion Injury
Wounds and Injuries
Reperfusion Injury
Myocardial Ischemia
Small Interfering RNA
Rats
Phosphorylation
Cell death
Cardiac Myocytes
Nitric Oxide
Cell Death
Chemical activation
Janus Kinase 2
STAT3 Transcription Factor
Gene Silencing

Keywords

  • Adiponectin
  • Antioxidants
  • Diabetes
  • Jak2/STAT3
  • Myocardial ischemia injury
  • PI3K/Akt

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

Cite this

N-Acetylcysteine and allopurinol up-regulated the Jak/STAT3 and PI3K/Akt pathways via adiponectin and attenuated myocardial postischemic injury in diabetes. / Wang, Tingting; Mao, Xiaowen; Li, Haobo; Qiao, Shigang; Xu, Aimin; Wang, Junwen; Lei, Shaoqing; Liu, Zipeng; Ng, Kwok F J; Wong, Gordon T.; Vanhoutte, Paul M.; Irwin, Michael G.; Xia, Zhengyuan.

In: Free Radical Biology and Medicine, Vol. 63, 2013, p. 291-303.

Research output: Contribution to journalArticle

Wang, Tingting ; Mao, Xiaowen ; Li, Haobo ; Qiao, Shigang ; Xu, Aimin ; Wang, Junwen ; Lei, Shaoqing ; Liu, Zipeng ; Ng, Kwok F J ; Wong, Gordon T. ; Vanhoutte, Paul M. ; Irwin, Michael G. ; Xia, Zhengyuan. / N-Acetylcysteine and allopurinol up-regulated the Jak/STAT3 and PI3K/Akt pathways via adiponectin and attenuated myocardial postischemic injury in diabetes. In: Free Radical Biology and Medicine. 2013 ; Vol. 63. pp. 291-303.
@article{3f069705a47148d5a0949af73aa7205c,
title = "N-Acetylcysteine and allopurinol up-regulated the Jak/STAT3 and PI3K/Akt pathways via adiponectin and attenuated myocardial postischemic injury in diabetes",
abstract = "N-Acetylcysteine (NAC) and allopurinol (ALP) synergistically reduce myocardial ischemia reperfusion (MI/R) injury in diabetes. However, the mechanism is unclear. We postulated that NAC and ALP attenuated diabetic MI/R injury by up-regulating phosphatidylinositol 3-kinase/Akt (PI3K/Akt) and Janus kinase 2/signal transducer and activator of transcription-3 (JAK2/STAT3) pathways subsequent to adiponectin (APN) activation. Control (C) or streptozotocin-induced diabetic rats (D) were untreated or treated with NAC and ALP followed by MI/R. D rats displayed larger infarct size accompanied by decreased phosphorylation of Akt, STAT3 and decreased cardiac nitric oxide (NO) and APN levels. NAC and ALP decreased MI/R injury in D rats, enhanced phosphorylation of Akt and STAT3, and increased NO and APN. High glucose and hypoxia/reoxygenation exposure induced cell death and Akt and STAT3 inactivation in cultured cardiomyocytes, which were prevented by NAC and ALP. The PI3K inhibitor wortmannin and Jak2 inhibitor AG490 abolished the protection of NAC and ALP. Similarly, APN restored posthypoxic Akt and STAT3 activation and decreased cell death in cardiomyocytes. Gene silencing with AdipoR2 siRNA or STAT3 siRNA but not AdipoR1 siRNA abolished the protection of NAC and ALP. In conclusion, NAC and ALP prevented diabetic MI/R injury through PI3K/Akt and Jak2/STAT3 and cardiac APN may serve as a mediator via AdipoR2 in this process.",
keywords = "Adiponectin, Antioxidants, Diabetes, Jak2/STAT3, Myocardial ischemia injury, PI3K/Akt",
author = "Tingting Wang and Xiaowen Mao and Haobo Li and Shigang Qiao and Aimin Xu and Junwen Wang and Shaoqing Lei and Zipeng Liu and Ng, {Kwok F J} and Wong, {Gordon T.} and Vanhoutte, {Paul M.} and Irwin, {Michael G.} and Zhengyuan Xia",
year = "2013",
doi = "10.1016/j.freeradbiomed.2013.05.043",
language = "English (US)",
volume = "63",
pages = "291--303",
journal = "Free Radical Biology and Medicine",
issn = "0891-5849",
publisher = "Elsevier Inc.",

}

TY - JOUR

T1 - N-Acetylcysteine and allopurinol up-regulated the Jak/STAT3 and PI3K/Akt pathways via adiponectin and attenuated myocardial postischemic injury in diabetes

AU - Wang, Tingting

AU - Mao, Xiaowen

AU - Li, Haobo

AU - Qiao, Shigang

AU - Xu, Aimin

AU - Wang, Junwen

AU - Lei, Shaoqing

AU - Liu, Zipeng

AU - Ng, Kwok F J

AU - Wong, Gordon T.

AU - Vanhoutte, Paul M.

AU - Irwin, Michael G.

AU - Xia, Zhengyuan

PY - 2013

Y1 - 2013

N2 - N-Acetylcysteine (NAC) and allopurinol (ALP) synergistically reduce myocardial ischemia reperfusion (MI/R) injury in diabetes. However, the mechanism is unclear. We postulated that NAC and ALP attenuated diabetic MI/R injury by up-regulating phosphatidylinositol 3-kinase/Akt (PI3K/Akt) and Janus kinase 2/signal transducer and activator of transcription-3 (JAK2/STAT3) pathways subsequent to adiponectin (APN) activation. Control (C) or streptozotocin-induced diabetic rats (D) were untreated or treated with NAC and ALP followed by MI/R. D rats displayed larger infarct size accompanied by decreased phosphorylation of Akt, STAT3 and decreased cardiac nitric oxide (NO) and APN levels. NAC and ALP decreased MI/R injury in D rats, enhanced phosphorylation of Akt and STAT3, and increased NO and APN. High glucose and hypoxia/reoxygenation exposure induced cell death and Akt and STAT3 inactivation in cultured cardiomyocytes, which were prevented by NAC and ALP. The PI3K inhibitor wortmannin and Jak2 inhibitor AG490 abolished the protection of NAC and ALP. Similarly, APN restored posthypoxic Akt and STAT3 activation and decreased cell death in cardiomyocytes. Gene silencing with AdipoR2 siRNA or STAT3 siRNA but not AdipoR1 siRNA abolished the protection of NAC and ALP. In conclusion, NAC and ALP prevented diabetic MI/R injury through PI3K/Akt and Jak2/STAT3 and cardiac APN may serve as a mediator via AdipoR2 in this process.

AB - N-Acetylcysteine (NAC) and allopurinol (ALP) synergistically reduce myocardial ischemia reperfusion (MI/R) injury in diabetes. However, the mechanism is unclear. We postulated that NAC and ALP attenuated diabetic MI/R injury by up-regulating phosphatidylinositol 3-kinase/Akt (PI3K/Akt) and Janus kinase 2/signal transducer and activator of transcription-3 (JAK2/STAT3) pathways subsequent to adiponectin (APN) activation. Control (C) or streptozotocin-induced diabetic rats (D) were untreated or treated with NAC and ALP followed by MI/R. D rats displayed larger infarct size accompanied by decreased phosphorylation of Akt, STAT3 and decreased cardiac nitric oxide (NO) and APN levels. NAC and ALP decreased MI/R injury in D rats, enhanced phosphorylation of Akt and STAT3, and increased NO and APN. High glucose and hypoxia/reoxygenation exposure induced cell death and Akt and STAT3 inactivation in cultured cardiomyocytes, which were prevented by NAC and ALP. The PI3K inhibitor wortmannin and Jak2 inhibitor AG490 abolished the protection of NAC and ALP. Similarly, APN restored posthypoxic Akt and STAT3 activation and decreased cell death in cardiomyocytes. Gene silencing with AdipoR2 siRNA or STAT3 siRNA but not AdipoR1 siRNA abolished the protection of NAC and ALP. In conclusion, NAC and ALP prevented diabetic MI/R injury through PI3K/Akt and Jak2/STAT3 and cardiac APN may serve as a mediator via AdipoR2 in this process.

KW - Adiponectin

KW - Antioxidants

KW - Diabetes

KW - Jak2/STAT3

KW - Myocardial ischemia injury

KW - PI3K/Akt

UR - http://www.scopus.com/inward/record.url?scp=84879473184&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84879473184&partnerID=8YFLogxK

U2 - 10.1016/j.freeradbiomed.2013.05.043

DO - 10.1016/j.freeradbiomed.2013.05.043

M3 - Article

C2 - 23747931

AN - SCOPUS:84879473184

VL - 63

SP - 291

EP - 303

JO - Free Radical Biology and Medicine

JF - Free Radical Biology and Medicine

SN - 0891-5849

ER -