Oxidative Stress, Dis-ease and the CellBio test

[Dr. Jeff]

Here's the beginning of a chapter from Braunwald's comprehensive cardiology 2011 textbook.

Later on, the authors discuss isoprostane which is what CellBio Hemet's test for oxidative stress) measures:

8-Isoprostanes are elevated in tissue subjected to increased oxidative stress, and can be extracted and measured quantitatively using several methods including an enzyme-linked immunoassay.

From: Heart Failure: A Companion to Braunwald's Heart Disease (Second Edition), 2011
Oxidative and Nitrosative Stress in Heart Failure

Douglas B. Sawyer, Chang-seng Liang, and Wilson S. Colucci

There is now evidence that oxidative stress is increased in heart failure, and experimental studies suggest that this may contribute to the structural and functional changes leading to disease progression.

Our understanding of the role of oxidative stress in myocardial dysfunction, though largely incomplete, continues to grow. In this chapter, we will review the evidence for increased oxidative stress in heart fail- ure, in vivo evidence suggesting a role for oxidative stress in the pathogenesis of heart failure, and recent in vitro studies that sug- gest potential mechanisms by which reactive oxygen species (ROS) (see Chapter 15) might mediate myocardial remodeling and contractile dysfunction (see Chapter 13) and have no overt myocardial phenotype.

As the only SOD located in the mitochondria, MnSOD plays a critical role in the con- trol of mitochondrial ROS generated during normal oxidative phosphorylation (see later discussion). The phenotype of the MnSOD knockout mouse therefore also underscores the importance of the mitochondria as a source of ROS in the myocardium.

H2O2, the product of SOD, is handled by one of several glutathione peroxidases (GPx) and/or catalase. GPx are selenium-containing enzymes that catalyze the removal of H2O2 through oxidation of reduced glutathione (GSH), which is recycled from oxidized glutathione (GSSG) by the NADPH-dependent glutathione reductase (GRed). The activity of GPx requires stoichiometric quantities of GSH, and therefore low levels of GSH reduce the activity of GPx. GRed requires NAD(P)H as a reductant to recycle GSSG to GSH.

In this context, enzymes in the pentose phosphate pathway and glucose-6-phosphate dehydro- genase (G6PD), the rate-limiting enzyme in this pathway, can be thought of as ancillary antioxidant enzymes that are critical to cel- lular antioxidant defenses. Other ancillary antioxidant enzymes are emerging that work through distinct mechanisms, such as heme oxygenase-I, which is induced by oxidative stress and serves a cytoprotective function through the breakdown of pro-oxidant heme into equimolar amounts of carbon monox- ide, biliverdin/bilirubin, and free ferrous iron. Carbon monoxide and bilirubin have been shown to exert direct cardioprotective effects via their respective antiin ammatory and antioxidant actions. Cardioselective overexpression of heme oxygenase-1 also has been shown to reduce infarct size, and in ammatory and oxidative damage, and attenuate postinfarct cardiac remodeling in animals after coronary artery occlusion and reperfusion injury.

GPx-1, like MnSOD, is encoded on the nuclear genome but localizes to the mito- chondria. Mice deficient in GPx-1 have no overt abnormality in myocardial function. GPx are selenium-containing enzymes,11 and dietary de ciency of selenium, as occurs in some areas of China, is associated with a dilated cardiomyopathy and heart failure. There is evidence of increased oxi- dative stress in selenium-defficient people.

Reactive oxygen species (ROS) are a by- product of aerobic metabolism, and so the highly metabolically active myocar- dium is rich in ROS. As in all tissues, ROS are handled in the myocardium by both soluble and enzymatic antioxidant systems. “Oxidative stress” occurs when the production of ROS exceeds the capacity of antioxidant defense sys- tems. ROS cascades begin with the formation of superoxide anion (O2−) by either enzymatic or nonenzymatic one electron reduction of molecular oxygen (Figure 12-1). The unpaired electron in O2− is an unstable free radical that reacts with itself and other oxygen-containing species, and directly or indirectly with organic molecules including lipids, nucleic acids, and proteins, ultimately lead- ing to disruption of cellular functions. All aerobic organisms, from bacteria to man, have evolved a complex antioxidant defense system of enzymatic and non- enzymatic components to defend against the unavoidable formation of ROS.1 In parallel there has been the evolution of speci c ROS-generating systems that are used both in the immune system, where the toxicity of ROS is exploited to ght infectious organisms2 and in all cell types where ROS act as signaling interme- diates for the purpose of triggering speci c intracellular changes in cell biology. Primary antioxidant enzymes (de ned here as those that directly interact with ROS) including superoxide dismutases (SOD), catalase, and peroxidases work in parallel with nonenzymatic antioxidants to protect cells and tissues from ROS. The mitochondrial enzymes manganese superoxide dismutase (MnSOD) and glutathione peroxidase (GPx) appear to be the most important in controlling myocardial levels of O2− and H2O2. Approximately 70% of the SOD activity in the heart, and 90% of that in the cardiac myocyte, is attributable to MnSOD (SOD2).3 The remainder consists of cytosolic Cu/ZnSOD (SOD1), with less than 1% contributed by extracellular-SOD (ECSOD, SOD3).4 This is in con- trast to other organs, where Cu/ZnSOD plays a greater role. The relative impor- tance of MnSOD in the regulation of oxidative stress in the myocardium is highlighted by the demonstration that homozygous knockout mice de cient in MnSOD develop normally in utero, but die soon after birth with dilated cardio- myopathy.5 In contrast, mice de cient in CuZnSOD or ECSOD grow normally