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A Systematic Review on the Protective Effect of N-Acetyl Cysteine Against Diabetes-Associated Cardiovascular Complications

  • Systematic Review
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American Journal of Cardiovascular Drugs Aims and scope Submit manuscript

Abstract

Introduction

Heart failure is the leading cause of death in patients with diabetes. No treatment currently exists to specifically protect these patients at risk of developing cardiovascular complications. Accelerated oxidative stress-induced tissue damage due to persistent hyperglycemia is one of the major factors implicated in deteriorated cardiac function within a diabetic state. N-acetyl cysteine (NAC), through its enhanced capacity to endogenously synthesize glutathione, a potent antioxidant, has displayed abundant health-promoting properties and has a favorable safety profile.

Objective

An increasing number of experimental studies have reported on the strong ameliorative properties of NAC. We systematically reviewed the data on the cardioprotective potential of this compound to provide an informative summary.

Methods

Two independent reviewers systematically searched major databases, including PubMed, Cochrane Library, Google scholar, and Embase for available studies reporting on the ameliorative effects of NAC as a monotherapy or in combination with other therapies against diabetes-associated cardiovascular complications. We used the ARRIVE and JBI appraisal guidelines to assess the quality of individual studies included in the review. A meta-analysis could not be performed because the included studies were heterogeneous and data from randomized clinical trials were unavailable.

Results

Most studies support the ameliorative potential of NAC against a number of diabetes-associated complications, including oxidative stress. We discuss future prospects, such as identification of additional molecular mechanisms implicated in diabetes-induced cardiac damage, and highlight limitations, such as insufficient studies reporting on the comparative effect of NAC with common glucose-lowering therapies. Information on the comparative analysis of NAC, in terms of dose selection, administration mode, and its effect on different cardiovascular-related markers is important for translation into clinical studies.

Conclusions

NAC exhibits strong potential for the protection of the diabetic heart at risk of myocardial infarction through inhibition of oxidative stress. The effect of NAC in preventing both ischemia and non-ischemic-associated cardiac damage is also of interest. Consistency in dose selection in most studies reported remains important in dose translation for clinical relevance.

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Abbreviations

AKT:

Protein kinase B

AMPK:

5′ AMP-activated protein kinase

Bak:

Bcl-2 antagonist/killer 1

Bax:

Bcl-2-like protein 4

Bcl-2:

B-cell lymphoma 2

Brg1:

Brahma-related gene

COX2:

Cyclooxygenase 2

CTGF:

Connective tissue growth factor

eNOS:

Endothelial nitric oxide synthase

ERK1/2:

Extracellular signal-regulated kinase 1 and 2

FoxO1:

Forkhead box protein O1

GSH:

Glutathione

HO-1:

Heme oxygenase 1

IL-6:

Interleukin 6

iNOS:

Inducible nitric oxide synthase

JBI:

Joanna Briggs Institute

JNK:

c-Jun N-terminal kinases

L-NAME:

N-ω-nitro-L-arginine methyl ester

NAC:

n-acetyl cysteine

NADPH:

Nicotinamide adenine dinucleotide phosphate

NF-kB:

Nuclear factor kappa-light-chain-enhancer of activated B cells

p38 MAPK:

p38 mitogen-activated protein kinases

p53:

Tumor protein p53

PERK:

Protein kinase RNA-like endoplasmic reticulum kinase

ROS:

Reactive oxygen species

SOD:

Superoxide dismutase

STAT3:

Signal transducer and activator of transcription 3

STZ:

Streptozotocin

UCF-101:

5-[5-(2-Nitrophenyl) furfuryliodine]-1,3-diphenyl-2-thiobarbituric acid

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Acknowledgements

The authors are indebted to Prof. Charles Shey Wiysonge of Cochrane South Africa for assistance with the development of this review.

Author information

Authors and Affiliations

  1. Biomedical Research and Innovation Platform (BRIP), South African Medical Research Council, Francie van Zijl Drive, P.O. Box 19070, Tygerberg, 7505, South Africa

    Phiwayinkosi V. Dludla, Stephanie C. Dias, Nnini Obonye, Rabia Johnson & Johan Louw

  2. Division of Medical Physiology, Faculty of Health Sciences, Stellenbosch University, Tygerberg, 7505, South Africa

    Rabia Johnson

  3. Department of Biochemistry and Microbiology, University of Zululand, KwaDlangezwa 3886, Richards Bay, South Africa

    Johan Louw

  4. School of Laboratory Medicine and Medical Sciences (SLMMS), College of Health Sciences, University of KwaZulu-Natal, Durban, 4000, South Africa

    Bongani B. Nkambule

Authors
  1. Phiwayinkosi V. Dludla
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  2. Stephanie C. Dias
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  3. Nnini Obonye
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  4. Rabia Johnson
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  5. Johan Louw
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  6. Bongani B. Nkambule
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Corresponding author

Correspondence to Phiwayinkosi V. Dludla.

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Funding

This study was funded by the Biomedical Research and Innovation Platform of the South Africa Medical Research Council (SAMRC). P.V. Dludla was partially supported as a Post-Doctoral Fellow by funding from the SAMRC. The SAMRC did not directly participate in the literature search, determination of study eligibility, data analysis, or interpretation or preparation of the manuscript for publication.

Conflict of interest

PVD, SCD, NO, RJ, JL, and BBN have no conflicts of interest that might be relevant to the contents of this manuscript.

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Dludla, P.V., Dias, S.C., Obonye, N. et al. A Systematic Review on the Protective Effect of N-Acetyl Cysteine Against Diabetes-Associated Cardiovascular Complications. Am J Cardiovasc Drugs 18, 283–298 (2018). https://doi.org/10.1007/s40256-018-0275-2

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  • DOI: https://doi.org/10.1007/s40256-018-0275-2

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