A Systematic Review on the Protective Effect of N-Acetyl Cysteine Against Diabetes-Associated Cardiovascular Complications
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.
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.
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.
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.
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.
Protein kinase B
5′ AMP-activated protein kinase
Bcl-2 antagonist/killer 1
Bcl-2-like protein 4
B-cell lymphoma 2
Connective tissue growth factor
Endothelial nitric oxide synthase
Extracellular signal-regulated kinase 1 and 2
Forkhead box protein O1
Heme oxygenase 1
Inducible nitric oxide synthase
Joanna Briggs Institute
c-Jun N-terminal kinases
N-ω-nitro-L-arginine methyl ester
Nicotinamide adenine dinucleotide phosphate
Nuclear factor kappa-light-chain-enhancer of activated B cells
- p38 MAPK
p38 mitogen-activated protein kinases
Tumor protein p53
Protein kinase RNA-like endoplasmic reticulum kinase
Reactive oxygen species
Signal transducer and activator of transcription 3
5-[5-(2-Nitrophenyl) furfuryliodine]-1,3-diphenyl-2-thiobarbituric acid
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
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.
- 2.WHO. World health statistics 2012. World Health Organization (WHO), 2012. http://apps.who.int/iris/bitstream/10665/44844/1/9789241564441_eng.pdf?ua=1. Accessed 20 Oct 2017.
- 3.WHO. The top 10 causes of death. 2017. http://www.who.int/mediacentre/factsheets/fs310/en/. Accessed 20 Oct 2017.
- 4.American Heart Association. Cardiovascular disease and diabetes. http://www.heart.org/HEARTORG/Conditions/More/Diabetes/WhyDiabetesMatters/Cardiovascular-Disease-Diabetes_UCM_313865_Article.jsp/#.WhVgWEqWaUk. Accessed 20 Oct 2017.
- 17.Camuglia AC, Maeder MT, Starr J, Farrington C, Kaye DM. Impact of N-acetylcysteine on endothelial function, B-type natriuretic peptide and renal function in patients with the cardiorenal syndrome: a pilot cross over randomised controlled trial. Heart Lung Circ. 2013;22(4):256–9.PubMedCrossRefGoogle Scholar
- 30.Institute The Joanna Briggs. Joanna Briggs Institute reviewers’ manual. 2016th ed. Australia: The Joanna Briggs Institute; 2016.Google Scholar
- 44.Abdel Baky NA, Mohamed AM, Faddah LM. Protective effect of N-acetyl cysteine and/or provitamin A against monosodium glutamate-induced cardiopathy in rats. JPT. 2009;4(5):178–93.Google Scholar
- 63.Liu ZW, Zhu HT, Chen KL, Dong X, Wei J, Qiu C, et al. Protein kinase RNA-like endoplasmic reticulum kinase (PERK) signaling pathway plays a major role in reactive oxygen species (ROS)-mediated endoplasmic reticulum stress-induced apoptosis in diabetic cardiomyopathy. Cardiovasc Diabetol. 2013;12:158.PubMedPubMedCentralCrossRefGoogle Scholar
- 70.Tuncay E, Okatan EN, Toy A, Turan B. Enhancement of cellular antioxidant-defence preserves diastolic dysfunction via regulation of both diastolic Zn2+ and Ca2+ and prevention of RyR2-leak in hyperglycemic cardiomyocytes. Oxid Med Cell Longev. 2014;2014:290381.PubMedPubMedCentralCrossRefGoogle Scholar
- 77.Wang S, Wang C. N-acetylcysteine attenuates diabetic myocardial ischemia reperfusion injury through inhibiting excessive autophagy. Mediat Inflamm. 2017;2017:9257291.Google Scholar