Accepted Manuscript Reversal of hyperglycemia: effects on nitric oxide signaling Cher-Rin Chong , B Pharm, Saifei Liu , MBBS, MBiotech, Giovanni Licari , PhD, Tamila Heresztyn , B Sc, Yuliy Y. Chirkov , PhD, Doan T. Ngo , PhD, John D. Horowitz , MBBS, PhD PII:
S0002-9343(14)01080-8
DOI:
10.1016/j.amjmed.2014.11.007
Reference:
AJM 12772
To appear in:
The American Journal of Medicine
Received Date: 21 October 2014 Revised Date:
5 November 2014
Accepted Date: 5 November 2014
Please cite this article as: Chong CR, Liu S, Licari G, Heresztyn T, Chirkov YY, Ngo DT, Horowitz JD, Reversal of hyperglycemia: effects on nitric oxide signaling, The American Journal of Medicine (2014), doi: 10.1016/j.amjmed.2014.11.007. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Title page
Title:
RI PT
Reversal of hyperglycemia: effects on nitric oxide signaling
Running title: Reversal of hyperglycemia restores NO signaling
SC
Article type:
Authors: Cher-Rin Chong; B Pharm Saifei Liu; MBBS, MBiotech Giovanni Licari; PhD Tamila Heresztyn; B Sc
Doan T Ngo; PhD
TE D
Yuliy Y Chirkov; PhD
M AN U
Brief Observations
John D Horowitz; MBBS, PhD
EP
Affiliations:
Cardiology and Clinical Pharmacology Department, Basil Hetzel Institute, the Queen Elizabeth Hospital
AC C
University of Adelaide, Adelaide, Australia
Author for correspondence: Professor John D Horowitz Cardiology Department, The Queen Elizabeth Hospital, 28, Woodville Road, Woodville, South Australia, AUSTRALIA, 5011. Tel: (61) 8-82226725; fax: (61) 8-82226422 email address: [email protected]
1
ACCEPTED MANUSCRIPT
Funding This study was partly funded by the Vascular Diseases and Therapeutics Research Group program grant. Cher-Rin Chong is a recipient of Australian Government National Health and Medical Research Council postgraduate scholarship. Saifei Liu is a recipient of Australian
RI PT
Postgraduate Award.
Conflict of interest:
SC
None
Acknowledgements
M AN U
The authors wish to acknowledge and thank the medical and nursing staff from the Cardiology department of The Queen Elizabeth Hospital for assistance in patient recruitment and sample collection.
Keywords:
Nitric oxide
TE D
Hyperglycemia
Endothelial progenitor cell
Thioredoxin-interacting protein
EP
Oxidative stress
AC C
Acute coronary syndrome
2
ACCEPTED MANUSCRIPT
Abstract
Background: Hyperglycemia in patients with acute coronary syndromes is associated with poor outcomes,
RI PT
and its rapid correction with insulin infusion has been shown to restore platelet responsiveness to nitric oxide (NO) and to suppress superoxide (O2-) generation. Thioredoxin-interacting protein (TXNIP) has recently emerged as a pivotal modulator of hyperglycemia-induced inflammation, O2- production and impairment of NO signaling, but it
SC
is not known whether its expression in platelets can be rapidly down-regulated.
Method:
M AN U
In twelve hyperglycemic acute coronary syndrome patients, we evaluated the putative role of TXNIP suppression in the platelet NO response after reversal of hyperglycemia with insulin infusion.
Results:
Insulin infusion for 13 ± 0.8 (SEM) hours decreased blood sugar level from 16.6 ± 1.6 to 8.7
TE D
± 1.4 mmol/L (p=0.002). This induced:
(1) sensitization of anti-aggregatory response to NO (from 6.5 ± 7.7 to 39.7 ± 7.0 %, p
S0002-9343(14)01080-8
DOI:
10.1016/j.amjmed.2014.11.007
Reference:
AJM 12772
To appear in:
The American Journal of Medicine
Received Date: 21 October 2014 Revised Date:
5 November 2014
Accepted Date: 5 November 2014
Please cite this article as: Chong CR, Liu S, Licari G, Heresztyn T, Chirkov YY, Ngo DT, Horowitz JD, Reversal of hyperglycemia: effects on nitric oxide signaling, The American Journal of Medicine (2014), doi: 10.1016/j.amjmed.2014.11.007. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Title page
Title:
RI PT
Reversal of hyperglycemia: effects on nitric oxide signaling
Running title: Reversal of hyperglycemia restores NO signaling
SC
Article type:
Authors: Cher-Rin Chong; B Pharm Saifei Liu; MBBS, MBiotech Giovanni Licari; PhD Tamila Heresztyn; B Sc
Doan T Ngo; PhD
TE D
Yuliy Y Chirkov; PhD
M AN U
Brief Observations
John D Horowitz; MBBS, PhD
EP
Affiliations:
Cardiology and Clinical Pharmacology Department, Basil Hetzel Institute, the Queen Elizabeth Hospital
AC C
University of Adelaide, Adelaide, Australia
Author for correspondence: Professor John D Horowitz Cardiology Department, The Queen Elizabeth Hospital, 28, Woodville Road, Woodville, South Australia, AUSTRALIA, 5011. Tel: (61) 8-82226725; fax: (61) 8-82226422 email address: [email protected]
1
ACCEPTED MANUSCRIPT
Funding This study was partly funded by the Vascular Diseases and Therapeutics Research Group program grant. Cher-Rin Chong is a recipient of Australian Government National Health and Medical Research Council postgraduate scholarship. Saifei Liu is a recipient of Australian
RI PT
Postgraduate Award.
Conflict of interest:
SC
None
Acknowledgements
M AN U
The authors wish to acknowledge and thank the medical and nursing staff from the Cardiology department of The Queen Elizabeth Hospital for assistance in patient recruitment and sample collection.
Keywords:
Nitric oxide
TE D
Hyperglycemia
Endothelial progenitor cell
Thioredoxin-interacting protein
EP
Oxidative stress
AC C
Acute coronary syndrome
2
ACCEPTED MANUSCRIPT
Abstract
Background: Hyperglycemia in patients with acute coronary syndromes is associated with poor outcomes,
RI PT
and its rapid correction with insulin infusion has been shown to restore platelet responsiveness to nitric oxide (NO) and to suppress superoxide (O2-) generation. Thioredoxin-interacting protein (TXNIP) has recently emerged as a pivotal modulator of hyperglycemia-induced inflammation, O2- production and impairment of NO signaling, but it
SC
is not known whether its expression in platelets can be rapidly down-regulated.
Method:
M AN U
In twelve hyperglycemic acute coronary syndrome patients, we evaluated the putative role of TXNIP suppression in the platelet NO response after reversal of hyperglycemia with insulin infusion.
Results:
Insulin infusion for 13 ± 0.8 (SEM) hours decreased blood sugar level from 16.6 ± 1.6 to 8.7
TE D
± 1.4 mmol/L (p=0.002). This induced:
(1) sensitization of anti-aggregatory response to NO (from 6.5 ± 7.7 to 39.7 ± 7.0 %, p
