Lesions and Lipids and Radicals —

adical is a word with many meanings. It is extreme, excellent, or exorbitant. It is a root word, a root number, or just a root. For most of us, radical describes a rather significant departure from the norm. In fact, you might classify as radical the publication of a basic science article (see Al-Ruzzeh and colleagues, page 127) with an accompanying editorial in the Texas Heart Institute Journal. In the lexicon of the cell biologist, reference to a radical is quite specific. It is an atom or molecule with at least 1 unpaired electron, capable of easy, enzymefree modification of neighboring molecular bonds. This radical and its contribution to vascular disease are the focus of discussion in these 2 articles. Because of their promiscuous nature, small molecules that are radicals or that are easily converted to radicals are loosely referred to as reactive species, subcategorized by their primary atom, oxygen or nitrogen (Table I). Reactive species are capable of oxidative modification or destruction of all cellular constituents, including lipids, proteins, and DNA. One can easily envision hydroxyl radicals or hypochlorous acid (common bleach) deforming DNA, corroding connective tissue, and participating in the explosive arterial injury that occurs during postischemic reperfusion. The presence of reactive species or oxidants in sufficient quantity to produce oxidized macromolecules is termed “oxidant stress. ” Radical injury—or oxidant stress —has been linked to the mechanism of aging, cancer, hypertension, ischemia– reperfusion injury, and atherosclerosis. A rational link between aging, cancer, degenerative diseases, and reactive species spawned a logical hypothesis: that fortifying our innate protective mechanisms with large quantities of willing victims of radical attack will impede the advance of these illnesses. Like little Dorothy from Kansas, this hypothesis was swept away from the dreary landscape of scientific rigor to the colorful land of Oz where vitamin E, vitamin C, and antioxidants of varied origin and combination are proffered to stem the tide of aging and atherosclerosis, stop skin from wrinkling, and even cure the common cold. Fantastic claims attract true believers from the depleted ranks of pyramidology and picketers of Area 51. Fortunately, skepticism dominates the minds of conservative physicians who have before them a plethora of clinical trials unable to offer proof of principle. The antioxidant debate rages with almost religious fervor in areas extending well beyond the scope of vascular disease. Meanwhile, HMG-CoA reductase inhibitors or statins have added new fuel to the fire of this debate. Their positive influence on a wide range of clinical conditions that are linked to oxidant stress is now accompanied by evidence of their antioxidant properties. Statin therapy reduces reactive oxygen species (ROS) generation and improves endothelial function as early as a few hours after the 1st dose. This timing implies effects unrelated to low-density lipoprotein (LDL) cholesterol concentrations. In today’s issue of the Texas Heart Institute Journal, Al-Ruzzeh and colleagues put cerivastatin to task, examining its ability to protect human endothelial cells in culture from hydrogen peroxide (H2O2) toxicity. Cell cultures were incubated with graded concentrations of H2O2 in combination with either cerivastatin or no protection, and the proportion of surviving cells was tabulated with disappointing results. The now discredited cerivastatin seemed to offer no protection from H2O2 at all. Taken at face value, these results challenge the newly forged reputation of the statins as antioxidants. Read face value as, “Pay no attention to the man behind the curtain. ” Measuring protection from H2O2-induced apoptosis may be useful in establishing the boundaries of statin benefit and allowing comparison to other “antioxidants” (vitamin C doesn’t perform very well under these study conditions either) but does not re-create the James M.Wilson, MD Brian Walton, MD