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

doi:10.1016/j.freeradbiomed.2013.05.043

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

Research output: Contribution to journal › Article › peer-review

75 Scopus citations

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 language	English (US)
Pages (from-to)	291-303
Number of pages	13
Journal	Free Radical Biology and Medicine
Volume	63
DOIs	https://doi.org/10.1016/j.freeradbiomed.2013.05.043
State	Published - 2013

Keywords

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

ASJC Scopus subject areas

Biochemistry
Physiology (medical)

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10.1016/j.freeradbiomed.2013.05.043

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Wang, T., Mao, X., Li, H., Qiao, S., Xu, A., Wang, J., Lei, S., Liu, Z., Ng, K. F. J., Wong, G. T., Vanhoutte, P. M., Irwin, M. G., & Xia, Z. (2013). N-Acetylcysteine and allopurinol up-regulated the Jak/STAT3 and PI3K/Akt pathways via adiponectin and attenuated myocardial postischemic injury in diabetes. Free Radical Biology and Medicine, 63, 291-303. https://doi.org/10.1016/j.freeradbiomed.2013.05.043

Wang, T, Mao, X, Li, H, Qiao, S, Xu, A, Wang, J, Lei, S, Liu, Z, Ng, KFJ, Wong, GT, Vanhoutte, PM, Irwin, MG & Xia, Z 2013, 'N-Acetylcysteine and allopurinol up-regulated the Jak/STAT3 and PI3K/Akt pathways via adiponectin and attenuated myocardial postischemic injury in diabetes', Free Radical Biology and Medicine, vol. 63, pp. 291-303. https://doi.org/10.1016/j.freeradbiomed.2013.05.043

@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",

note = "Funding Information: This work was supported by Research Grants Council (RGC) of Hong Kong GRF grants ( 781109M , 766709M , 784011 ) and the National Natural Science Foundation of China ( 81200609 ). The authors are grateful to Dr. Xia Gao (Department of Endocrinology, Beijing Chaoyang Hospital Affiliated to Capital Medical University, Beijing, China) for her assistance in echocardiography in this study. Dr. Zhengyuan Xia takes full responsibility for the work as a whole, including the study design, access to data, and the decision to submit and publish the manuscript. The authors declare no conflict of interest.",

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

N1 - Funding Information: This work was supported by Research Grants Council (RGC) of Hong Kong GRF grants ( 781109M , 766709M , 784011 ) and the National Natural Science Foundation of China ( 81200609 ). The authors are grateful to Dr. Xia Gao (Department of Endocrinology, Beijing Chaoyang Hospital Affiliated to Capital Medical University, Beijing, China) for her assistance in echocardiography in this study. Dr. Zhengyuan Xia takes full responsibility for the work as a whole, including the study design, access to data, and the decision to submit and publish the manuscript. The authors declare no conflict of interest.

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

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AN - SCOPUS:84879473184

SN - 0891-5849

VL - 63

SP - 291

EP - 303

JO - Free Radical Biology and Medicine

JF - Free Radical Biology and Medicine

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

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