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American Journal of Cardiovascular Drugs

, Volume 18, Issue 4, pp 283–298 | Cite as

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

  • Phiwayinkosi V. Dludla
  • Stephanie C. Dias
  • Nnini Obonye
  • Rabia Johnson
  • Johan Louw
  • Bongani B. Nkambule
Systematic Review

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.

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

Notes

Acknowledgements

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

Compliance with ethical standards

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.

Supplementary material

40256_2018_275_MOESM1_ESM.docx (36 kb)
Supplementary material 1 (DOCX 36 kb)

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Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Phiwayinkosi V. Dludla
    • 1
  • Stephanie C. Dias
    • 1
  • Nnini Obonye
    • 1
  • Rabia Johnson
    • 1
    • 2
  • Johan Louw
    • 1
    • 3
  • Bongani B. Nkambule
    • 4
  1. 1.Biomedical Research and Innovation Platform (BRIP)South African Medical Research CouncilTygerbergSouth Africa
  2. 2.Division of Medical Physiology, Faculty of Health SciencesStellenbosch UniversityTygerbergSouth Africa
  3. 3.Department of Biochemistry and MicrobiologyUniversity of ZululandRichards BaySouth Africa
  4. 4.School of Laboratory Medicine and Medical Sciences (SLMMS), College of Health SciencesUniversity of KwaZulu-NatalDurbanSouth Africa

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