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Prof. Mateja Kaja Jezovnik
Prof. Pavel Poredos ,
Oxidative stress, characterised by an increased production of free oxygen radicals, represents one of the basic pathogenetic processes of atherosclerosis and is closely related to endothelial dysfunction and promotes vascular inflammatory response.
Oxygen, the most critical nutrient for life, is the main source of free radicals or reactive oxgen species (ROS). Free radicals are highly reactive oxygen fragments which are created by normal chemical processes in the cells. During cellular respiration, some oxygen molecules are converted into free radicals and are characterised by the loss of one electron in the molecules. These hyperactive molecules would quickly enter into oxidative reactions with different vital cellular components containing lipids, proteins, nucleic acids and carbohydrates. Increased production of free radicals in the body is known as oxidative stress (1).
Free radicals are continuously formed as a consequence of many oxidative chemical reactions in the body. In addition, the environment is also a source of free radicals; this includes: ionizing radiation, ozone and nitrous oxide, heavy metals (mercury, cadmium, lead), cigarette smoke, alcohol consumption. Numerous experimental and clinical studies have demonstrated that common conditions predisposing to atherosclerosis such as hypercholesterolemia, hypertension, diabetes and smoking are also associated with an increased production of Reactive Oxygen Species (ROS) (2).
Reactive oxygen species have been implicated as key processes of atherosclerosis, including oxidative modification of low density lipoprotein and endothelial dysfunction, thereby promoting a vascular inflammatory response. Angiotensin II is a major stimulator of vascular reactive oxygen species production. Angiotensin II stimulates the production of the ROS from both arterial smooth muscle cells and endothelial cells. Thus, there is substantial evidence implicating that vascular NADPH oxidase stimulated, at least in part, by angiotensin II is a major vascular source of ROS in atherosclerosis (3).
More recent data also show that ROS is critically involved in angiotensin II inducing pro-inflammatory effects in vascular cells. In endothelial cells, the expression of the leucocyte adhesion molecules VCAM–1 is potently induced by angiotensin II (4). These data support the hypothesis that ROS formation is critical for vascular inflammation – basic pathogenetic mechanism of atherosclerosis.
Numerous experimental and clinical studies have demonstrated that oxidant stress is closely related to different risk factors of atherosclerosis such as hypercholesterolemia, hypertension, diabetes and smoking. Oxidant stress caused by risk factors is a major cause of endothelial dysfunction as a common condition predisposing to atherosclerosis.
LDL cholesterol – the hypothesis that oxidant stress plays an important role in atherogenesis was suggested by the observation that LDL has to be modified before it becomes atherogenic. Increased oxidative stress and related superoxide anion formation in vascular cells promote conversion of LDL to more atherogenic oxidised LDL (ox-LDL). Also ox-LDL itself has been identified as a potent stimulus of vascular oxigen radical formation increasing oxidative stress and contributing to the inflammatory state of atherosclerosis (5). Oxidatively modified LDL is one of the most extensively studied modifications and was recognized as a marker of oxidative stress.
Hypertension - since atherosclerosis should be accepted fundamentally as inflammatory disease, atherogenic stimuli like hypertension appear to activate the inflammatory response through oxidative stress by causing expression of mononuclear leucocyte recruiting mechanisms. The gene for one of these, the vascular cell adhesion molecule–1, is controlled in part by transcriptional factors regulated by oxidative stress, which modifies the redox state of the endothelial cell. There is also evidence that hypertension may exert oxidative stress directly on the arterial wall and predispose to and accelerate atherosclerosis. Increased production of oxidants such as superoxide anion can cause superoxide to rise, decreasing nitric oxide availability for smooth muscle relaxation. Hydrogen peroxide and superoxide can also increase endothelin-1 synthesis, which results in vasoconstriction and increased blood pressure (6, 7).
Diabetes – In patients with diabetes there is increased peroxidation of LDL. Increased autooxidation of cholesterol was observed also in patients with type 2 diabetes and normal level of cholesterol (8).
Smoking – Cigarette smoke contains abundant free radical species and reactive oxidants such as hydrogen peroxide (H2O2). That smoking is a common mechanism for generating oxidative stress and inflammation was shown in different studies. In the study from Agarwal it was shown that smokers have an increased level of different markers of oxidative stress including malondialdehyde (MDA) in plasma and urine (9, 10).
On the other hand, studies indicated that in patients with different atherosclerotic diseases there is an increased level of proinflammatory cytokines and markers of oxidative stress. We showed that in patients with peripheral arterial occlusive disease, ischaemia, during intermittent claudication, provokes an endothelial dependent functional deterioration of arterial circulation which is related to the increased oxidative stress. Therefore, oxidative stress with coupled inflammatory response is most probably a common pathway of harmful effects of risk factors for atherosclerosis on a vessel wall, and in patients with atherosclerotic disease it promotes progression of the disease.
It is expected that preventive and therapeutic measures of atherosclerosis influence basic pathogenetic mechanisms of atherosclerosis including inflammation and oxidative stress. There are some data that drugs used in secondary prevention of atherosclerosis - angiotensin-converting enzyme – inhibitors (ACE-I) and calcium channel blockers - have antioxidant properties and that their vascular defence effect is related to reduced oxidant stress. Different studies indicated that the inhibition of ACE may reduce vascular oxidant stress by preventing activation of the vascular oxidant enzyme systems, particularly the membrane-associated, NADH-dependent oxidase. In addition, ACE inhibition restores the activity of endogenous vascular antioxidant defence system, extracelullar superoxide dismutase in patients with coronary disease (4). These results suggest that inhibition of vascular ROS production may importantly contribute to vascular protective effects of ACE inhibitors such as was observed in the HOPE study. On the other hand, different vitamins, especially vitamin E – known »antioxidant« failed to show a significant beneficial effect on cardiovascular events. There are several explanations for inefficiency of vitamin E in clinical trials. First, the rate constant for reaction between vitamin E and superoxide is 5-6 orders of magnitude less than the reaction of superoxide with nitrogen oxide (NO). Second, vitamin E is concentrated in lipid membranes and lipoproteins. As many of the oxidative events that may be important in atherosclerosis occur in the cytoplasm, the extra cellular space would not be affected by lipid soluble antioxidants. Third, upon scavenging a radical, vitamin E becomes tocopheroxyl radical which can, under certain circumstances, enhance lipid peroxidation (11, 12). Therefore, ACE inhibition may represent a much more efficient way to prevent detrimental effects of vascular oxidant stress than trying to scavenge free radicals using vitamins.
The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.
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Prof. P. Poredos, and Dr M. Kaja Ježovnik Ljubljana, Slovenia Past-chairman of the WG on Peripheral Circulation
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