Good stress, bad stress--the delicate balance in the vasculature

Abstract

Background: Radicals have important physiological functions, for example, in immune defense and vasoprotection. However, they are also potentially dangerous waste products of cellular metabolism and they can contribute to the development of many different diseases.

Method: Selective literature review.

Results: The scientific understanding of radicals has not yet led to any therapeutic application. For many years, scavenging already formed radicals with antioxidants was considered to be the most promising therapeutic approach, but clinical trials based on this principle have yielded mostly negative results. Thus, entirely new approaches are needed. The goal should be to prevent the formation of harmful radicals, or to treat radical-related damage if it has already occurred. New diagnostic tools have the potential to identify those patients that are most likely to benefit from this form of treatment, as well as to document its success.

Conclusions: A new generation of cardiovascular drugs is being developed for the prevention or the mechanism-based treatment of vascular damage caused by oxidative stress. This new therapy should go hand in hand with new diagnostics, in accordance with the principle of individualized medicine.

Keywords: antioxidants; nitric oxide; oxidative stress; radicals; vascular diagnostics.

Figure 1

Reactive oxygen species (ROS). Oxygen can be activated in several reductive steps into the superoxide radical O2– or hydrogen peroxide (H2O2). The second step can occur spontaneously or be catalyzed by superoxide dismutase (SOD). Hydrogen peroxide is detoxified by catalase (Cat) into oxygen and water. If superoxide and hydrogen peroxide interact with nitric oxide (NO) or nitrite (NO2–), peroxynitrite (ONOO^–) is generated. Peroxynitrite can oxidize different cellular components and nitrate proteins. Nitrated proteins are biomarkers for oxidative stress. Red indicates disease promoting proteins or compounds; green, protective factors; arrows, reactions or transformations; a box indicates a protein—for example, an enzyme or receptor. The processes shown within the grey area occur naturally in the body. Oxygen needs to be obtained exogenously by respiration.

Figure 2

Enzymatic sources of ROS, their effects and pharmacological modulation. NO synthases (NOS) generate nitric oxide (NO) from the amino acid arginine. NO activates soluble guanylate cyclase (sGC), which mediates its protective effects. sGC generates the second messenger cyclic GMP (cGMP). The phosphorylation of the cGMP dependent protein kinase substrate vasodilator stimulated phosphoprotein (VASP) is a biomarker for this signaling pathway. Angiotensin II (Ang II) induces oxidative stress by activating NADPH oxidases (NOX). ROS generated by NOX result, among others, in accumulation of the arginine derivate asymmetric dimethyl arginine (ADMA), an endogenous inhibitor of NOS. Furthermore, NOS is oxidized and “uncoupled” by ROS. Uncoupled NOS generates ROS instead of NO. Additionally, ROS oxidize the NO receptor sGC (ox sGC). In this process, the heme group of the sGC is oxidized first, and in a second step this group is then released from sGC resulting in heme free (apo-)sGC, which cannot be activated by NO. Apo-sGC can be reactivated by sGC activators. sGC stimulators affect non-oxidized sGC. They allow maximum sGC activity even in the presence of reduced NO concentrations. Red indicates disease promoting proteins or compounds; green, protective factors; arrows, reactions or transformations; arrows with +, stimulation or activation; a line with a rectangle, inhibition; a box indicates a protein—for example, and enzyme or a receptor. The processes within the grey area occur in the body endogenously; the ones outside thee grey area indicate exogenous factors or drugs.