Oxidative stress as a mediator of cardiovascular disease

Abstract

During physiological processes molecules undergo chemical changes involving reducing and oxidizing reactions. A molecule with an unpaired electron can combine with a molecule capable of donating an electron. The donation of an electron is termed as oxidation whereas the gaining of an electron is called reduction. Reduction and oxidation can render the reduced molecule unstable and make it free to react with other molecules to cause damage to cellular and sub-cellular components such as membranes, proteins and DNA. In this paper, we have discussed the formation of reactive oxidant species originating from a variety of sources such as nitric oxide (NO) synthase (NOS), xanthine oxidases (XO), the cyclooxygenases, nicotinamide adenine dinucleotide phosphate (NAD(P)H) oxidase isoforms and metal-catalysed reactions. In addition, we present a treatise on the physiological defences such as specialized enzymes and antioxidants that maintain reduction-oxidation (redox) balance. We have also given an account of how enzymes and antioxidants can be exhausted by the excessive production of reactive oxidant species (ROS) resulting in oxidative stress/nitrosative stress, a process that is an important mediator of cell damage. Important aspects of redox imbalance that triggers the activity of a number of signalling pathways including transcription factors activity, a process that is ubiquitous in cardiovascular disease related to ischemia/reperfusion injury have also been presented.

Figure 1

In physiological and disease states, the involvement of the inflammatory state initiated within cellular environment. This entails increased activities of antioxidant enzymes and other antioxidant defences to counteract occurrence of oxidative stress mainly characterised by nitric oxide (NO) and reactive oxygen species (ROS). This molecular fiasco illustrates into cellular pathways that regulate redox status of cells and the consequence of imbalance between free radical production and antioxidant activity during the cardiovascular disease process.

Figure 2

Several interlinked pathways that include mitochondria respiration, NADPH oxidases, xanthine oxidase and uncoupled NO synthases are associated with the production of free radicals within cells under physiological conditions. Mitochondria produce significant amounts of cellular ROS via aberrant O₂ reaction. This rate of mitochondrial respiration and ROS formation is largely influenced by the coupling state of the mitochondria, and in turn by factors such as internal and external Ca²⁺ levels and antioxidant activity. In response to the presence of respiratory burst explained in the text, NADPH oxidase activity get modulated by upregulation of component mRNAs and other inflammatory mediators such as TNFalpha thus dependent on the increase in transcription of p22phox, an important subunit of NAD(P)H oxidase.

Figure 3

Proposed mechanism of xanthine oxido-reductase pathways. The enzymatic inhibition results in an increased availability of hypoxanthine for purine nucleotide synthesis via 5′-nucleotidase and inosine monophosphate (IMP) and adenosine monophosphate (AMP) dephosphorylation, thereby facilitate dissipating adenosine triphosphate (ATP) synthesis. On one hand, transmembrane ion gradients push cytosolic concentrations of calcium to rise, which in turn, activities protease that irreversibly converts xanthine dehydrogenase (XDH), predominant in vivo, in to xanthine oxidase (XO). At the same time, cellular ATP is catabolised to hypoxanthine, which accumulates in the diseased cell. During the reperfusion phase, XO using readmitted oxygen and hypoxanthine generates superoxide and hydrogen peroxide. Scheme derived from Puig et al., 1989.

Figure 4

Recent emerging work supports with more overt evidence thus showing the strong relation of human disease mechanisms to the production of reactive oxidant species and the dysregulation of oxidantantioxidants pathways. These pathways as discussed in this review demonstrate the modulation of signal transduction processes and energy metabolism in response to conditions of oxidative/nitrosative stress.