Cardiovascular diseases (CVD) are the leading cause of death and disability worldwide. Cardiovascular disease usually affects older people. Age is of course an important risk factor, but the main causes of CVD begin early in life and the risk factors could probably dramatically be decreased with life style changes including exercise and healthy food. The present situation, however with a growing population of older citizens the socio-economic costs connected to CVD is increasing dramatically. Individuals as well as the health care systems of the societies are under a heavy burden and there is a medical and diagnostic need to meet this situation. Overall, CVD cost the EU economy €192 billion each year. Of the total costs, 57% fall on health care costs, 21% on productivity losses and 22% on informal care of patients.
During 20 years there has been a disappointing lack of development for new efficient diagnostic tools and medical drugs that could meet this need for improvement. Only a single drug exists for therapy of stroke that is the leading cause of cardiovascular death. All current drugs circle more or less around the same limited mechanisms of action, (a) vasodilatation via the renin-angiotensin-aldosterone system, diuretics (with unknown mechanisms of action beyond the initial diuresis) and calcium channel blockade, (b) cholesterol lowering (but probably with important anti-inflammatory off-target effects that may be even more relevant than cholesterol lowering), beta-blockers (with many suggested but no proven mechanisms). Similarly, classical diagnostic and drug discovery approaches have yielded no or only very few successes in the past years.
Genetic and preclinical studies now point to surprising, unexpected pathomechanisms related to T-cells and innate immune response mechanisms and oxidative burst enzymes, such as NADPH oxidases expressed also in non-immune cells. Oxidative stress, an increase in reactive oxygen species (ROS), is a likely fundamental disease mechanism contributing to CVD. Accordingly, the literature often claims that antioxidant supplements prevent or cure these diseases. However, this strategy of counteracting oxidative stress, i.e. attempting to scavenge ROS after their generation, has not resulted in any beneficial clinical outcomes but supplemented antioxidants may even be harmful. There are several explanations for this. Instead of allowing ROS to form and then attempt to scavenge them, prevention of pathological ROS formation should be more effective. Selective inhibition of only those enzymes that overproduce ROS would leave physiological ROS formation intact. For example, untargeted scavenging of ROS interferes with their essential functions such as the ‘oxidative burst’, the release of high ROS amounts from neutrophils as part of the innate immune response. In lower, tightly regulated concentrations, ROS are physiologic signalling molecules regulating e.g. cell proliferation and angiogenesis. Several enzymes can generate ROS, including xanthine oxidase, cyclooxygenases, uncoupled endothelial nitric oxide synthase (eNOS), and mitochondrial enzymes. NADPH oxidases stand out as the only enzymes solely dedicated to ROS production. Other enzymes produce ROS as a by-product. NADPH oxidases are thus prime candidates as disease-relevant sources of ROS and thus they represent a highly promising class of drug targets.
Damage due to lack of oxygen, so-called ischemic injury in the heart and other organs, most often caused by atherosclerosis in the vessels, are important in the development of disease of the heart and blood vessels, both in the acute situation, such as myocardial infarction or stroke, or chronic, for example heart failure. An impaired perfusion is a central pathologic mechanism and treatment of myocardial infarction with such catheter dilation of blood vessels or the dissolution of blood clots (thrombolysis) focuses on restoring blood flow.
NADPH oxidase system catalyzes the NADPH-dependent reduction of molecular oxygen to superoxide anions, which are then dismuted to hydrogen peroxide. Today the Nox family consists of seven members: Nox1 – 5 and Duox1 and Duox2. In a recently published paper Matsushima and colleagues show that the two most important Nox forms for the production of O2-and H2O2 in the heart is Nox2 and Nox4. They also describe that the two complexes play an important role in mediating oxidative stress and damage to the heart muscle and blood vessels during infarction and reperfusion. Nox2 is involved in remodeling of heart function after an attack while Nox4 is a critical factor in mitochondrial oxidative stress and mitochondrial dysfunction in heart failure.