Regulatory role of peroxynitrite in advanced glycation end products mediated diabetic cardiovascular complications

Asis Bala

Abstract The Advanced Glycation End Products (AGE) binding with its receptor can increase reactive oxygen species (ROS) generation through specific signaling mediators.The effect of superoxide (O2-) and O2- mediated ROS and reactive nitrogen species depends on their concentration and location of formation.Nitric oxide (NO) has anti-inflammatory and anticoagulant properties and a vasodilation effect,but NO can be deactivated by reacting with O2-.This reaction between NO and O2- produces the potent oxidant ONOO-.Therefore,ONOO-'s regulatory role in AGEs in diabetic cardiovascular complications must considered as a regulator of cardiovascular complications in diabetes.

Key Words: Diabetes;Cardiovascular complication;Advanced glycation end products;Reactive oxygen species;Reactive nitrogen species;Peroxynitrite

TO THE EDlTOR

I am writing to express my appreciation for the article published by Bansalet al[1] in theWorld Journal of Diabetesin 2023,titled ＂Advanced glycation end products: Key mediator and therapeutic target of cardiovascular complications in diabetes＂.The article provides a clear explanation of the role of Advanced Glycation End Products (AGE) in cardiovascular complications.

I want to draw attention to the role of superoxide (O2-) in connection to AGE,reactive oxygen species (ROS),and reactive nitrogen species (RNS) mediated immune inflammation.The article comprehensively outlined the impact of AGE on diabetic cardiovascular disease,encompassing both cellular and extracellular pathological effects.These effects include extracellular matrix oxidation,glycation of low-density lipoprotein,and the triggering of inflammatory signaling cascades,such as NADPH oxidase,NRF-2,NFκB,JAK,and STAT pathways.On the contrary,the article partially emphasized the significant role of Nitric oxide (NO) and NO synthase (NOS) in regulating AGE formation.

As mentioned in the article,AGE binding with its receptor increases ROS generation through stimulation of specific signaling mediators such as ERK,phospholipase A2,phosphoinositide 3-kinase activation,activation of NADPH oxidase,inducible NOS,PKC,and p38 MAPK[2].However,the beneficial or detrimental role of O2-and O2--mediated ROS or RNS is determined by its concentration and the places where it is formed[3].Studies have shown that O2-immediately interacts with NO to produce the highly toxic peroxynitrite (ONOO-),which plays a crucial role in vascular changes in diabetic cardiovascular complications[4,5].

The damage to vascular endothelial cells is a leading cause of diabetic vascular complications,which can be combated using endothelial progenitor cells (EPCs)[6].The activation of various pathways such as xanthine and NAD(P)H oxidases,uncoupled NOS,cyclooxygenase,glucose autoxidation,the mitochondrial respiratory chain,polyol,and AGEs is triggered by hyperglycemia[4,7].These pathways lead to the production of superoxide anion (O2-)[4,5].The generation of superoxide due to hyperglycemia can also increase NO generation by enhancing the expression of NOSs by activating NF-κB[8].However,O2-can quench NO,reducing the efficacy of the endothelium-derived vasodilator system[4].Moreover,superoxide dismutase can convert superoxide to hydrogen peroxide (H2O2),which can react further with NO to form ONOO-[9].ONOO-can cause damage to cells by initiating lipid peroxidation,inactivating enzymes and proteinsviaoxidation and nitration,and activating matrix metalloproteinases[10].Additionally,ONOO-can decrease the membrane potential by acting on mitochondria,triggering the release of proapoptotic factors such as cytochrome c and apoptosis-inducing factor[4,9,10].These factors can mediate caspase-dependent and -independent apoptotic death pathways,which may contribute to the progression of diabetic cardiovascular complications[4].Therefore,ONOO-is considered one of the critical modulators of diabetic cardiovascular complications since high glucose levels can impair EPC function and reduce NO production.

Furthermore,NADPH oxidase-derived ROS have become critical regulators of host immune responses and cellular inflammation[11,12].Activation of phospholipase A2 in human neutrophils and other inflammatory cells by polyunsaturated fatty acids stimulates O2-production,triggering innate immune reactions.Increased O2-production may also activate the arachidonic acid pathways[5].Oxygen undergoes a series of univalent reductions,sequentially producing O2-,H2O2,etc.NO always shows its anti-inflammatory,anticoagulant properties and vasodilation effect.Still,it can be inactivated by reaction with O2-,producing the potent oxidant ONOO-[11-13].Therefore,the regulatory role of ONOO-in AGEs in diabetic cardiovascular complications also needs to be considered.

FOOTNOTES

Author contributions:Bala A solely planned and wrote the manuscript.

Conflict-of-interest statement:No conflict of interest to declare.

Open-Access:This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers.It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license,which permits others to distribute,remix,adapt,build upon this work non-commercially,and license their derivative works on different terms,provided the original work is properly cited and the use is non-commercial.See: https://creativecommons.org/Licenses/by-nc/4.0/

Country/Territory of origin:India

ORClD number:Asis Bala 0000-0002-2148-2331.

S-Editor:Lin C

L-Editor:A

P-Editor:Chen YX