Free radicals: should clinicians pay attention to them?

The Radical-Free Corner by Protasio L. da Luz*

Within the Cepid-Redoxoma, we are deeply involved in redox research and we consider this very important, of course. However, it is interesting at times to see how some meaningful outsiders interpret the area. The Radical-Free Corner challenged a highly experienced academic clinician-scientist, who kindly accepted this task (he happens to have been the Editor’s doctorate supervisor – a minor conflict of interest, I confess)

(Editor's comment)

Oxidative stress pervades several areas of Medicine: aging, cancer, atherosclerosis and other degenerative conditions, principally. Several studies claim that it is the cause of aging. But while there is evidence for oxidative footprints in aged cells [1], this seems far from being the end of the story. Recently, for instance, Gladyshev [2] questioned this theory and suggested that oxidative stress is only part of a general process of biological imperfectness, in which several players are involved in aging and the whole process is influenced by many variables such as species or environmental circumstances. In atherosclerosis, several evidences indicate the importance of oxygen species in vascular pathophysiology. For instance, inactivation of NO by superoxide impairs arterial vasodilation and LDL oxidation is recognized as a fundamental mechanism in foam-cell formation and plaque development. There is even a specific receptor in macrophages to which oxidized LDL binds - LOX-1.

Oxidative stress is traditionally regarded as an imbalance between reactive oxygen species (ROS) production and their inactivation - or removal by natural antagonists (superoxide dismutase, for instance). The distinct ROS include some highly reactive chemicals that act upon specific molecular sites of proteins and other cellular chemical constituents, altering cellular signaling pathways in a way to interfere with their function. They are ubiquitous and inherent to essentially all living species. This fact by itself makes one think that reactive species might to a good extent be necessary, because nature does not do silly things; we believe there is always a purpose.

One characteristic of redox systems is that they are confined to specific compartments and organelles, such as mitochondria, endoplasmic reticulum and others. This makes them specially difficult to approach from a therapeutic point of view. There are thousands of sites where redox processes occur. Which of them participates in one specific disease, plus when or how, is far from well understood. Also, redox systems are part of the defense mechanisms of the human body, for ex., in killing pathogenic bacteria. Further, many if not most of the informations we have today are derived from in vitro experiments in cultured cells, or in non-human species. Although homology is a feature of living beings, even small genetic differences make huge distinction between phenotypes, such as between men and rats. As a consequence, it is not entirely clear how many of these experimental findings are relevant to men.

Given these characteristics, some relevant clinical questions remain:

1. what is the real contribution of oxidative stress to the pathophysiology of human diseases? Are they the cause, a marker or just an epiphenomenon?
2. do chemical measurements in plasma reflect intracellular phenomena?
3. can specific targets be identified? can these targets be reached with present therapeutic agents?

One disturbing observation comes from lessons of populations who live longest under natural conditions such as the Japanese from Okinawa. They never even heard of supplemental antioxidants and just adhere to a healthy life with appropriate food, exercise, religion, no smoking, no stress and long lasting family ties. Furthermore, when controlled studies with antioxidant vitamins were performed in high-risk patients such as in the HOPE trial [3] (in which 9542 men and women randomly received vitamin E or placebo for 4.5 years), results were bluntly negative. Those complex physiopathological issues and disappointing clinical results generate skepticism among doctors and in practice put anti-oxidants aside. Should clinicians just forget about this?

Following from basic research, at the end it is essentially required that good clinical, randomized trials are addressed towards answering these questions. A possibly informative trial would be to assess the effects of an innovative anti-oxidant upon the intima of coronary arteries in patients with stable coronary disease, using Optical Coherence Tomography (OCT), which is a recent, very sensitive method to analyse the intima; a specific question could be: “does an anti-oxidant prevents progression of coronary atherosclerosis?”. While being a surrogate variable to clinical events, OCT measurements are a powerful indicator. If such trials result negative, it would not be the first time. Hormone replacement therapy, e.g., is just as well firmly justified according to countless experimental studies; however, it only does not work when applied to women! It reminds me of the old story: “According to the laws of aerodynamics the bumblebees cannot fly. The extension of their wings and disproportionate body weight makes flying impossible, as it can be easily demonstrated in a wind tunnel. However, being unaware of these scientific facts, the bumblebee does fly and makes some honey too” . Or as Shapeskeare said: “There are more things in heaven and earth, Horatio, than are dreamt of in your philosophy”. (Hamlet 1.5.167-8) Hamlet to Horatio.

1. D. P. Jones Redox theory of aging. Redox Biology, 5: 71-9, 2015. | dx.doi.org/10.1016/j.redox.2015.03.004
2. V. N. Gladyshev The free radical theory of aging is dead. Long live the damage theory! Antioxidants & Redox Signaling, 20 (4): 727-731, 2014. | dx.doi.org/10.1089/ars.2013.5228
3. S. Yusuf, G. Dagenais, J. Pogue, J. Bosch, P. Sleight. Vitamin E supplementation and cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. The New England Journal of Medicine, 342 (3): 154-60, 2000. | dx.doi.org/10.1056/nejm200001203420302

*Protasio Lemos da Luz, MD, FACC Senior Professor of Cardiology, Heart Institute (InCor), School of Medicine, Faculty of Medicine, University of São Paulo, Brazil e-mail: protasio.luz@incor.usp.br