Óxido nítrico sintase neuronal (nNOS) na doença arterial coronariana humana: correlação com a formação da placa aterosclerótica

Abstract

Coronary artery disease (CAD) is characterized by inadequate blood supply to the heart muscle, resulting from the narrowing of the arteries, mostly caused by atherosclerosis. Atherosclerosis, a chronic inflammatory process that promotes vascular remodeling and thrombus formation, is the major risk factor for acute myocardial infarction. Endothelial dysfunction is considered the initial event of a series of inflammatory diseases, such as atherosclerosis, characterized by a reduction in the bioavailability of vasoactive factors, especially Nitric Oxide (NO), increasing the tendency to vasoconstriction, greater thrombogenicity and abnormal cell proliferation. Neuronal nitric oxide synthase (nNOS) is an isoform of NOS that plays an important role in the vascular pathophysiology. Several studies in murine and human models have shown that the vascular expression of nNOS increases with plaque progression. However, the role of nNOS in the pathophysiology of atherosclerosis remains unclear. An apoE-/- animal study showed that the nNOS gene deletion accelerates plaque formation, suggesting an anti-atherogenic effect. There are still no studies on the role of nNOS in atherogenesis in humans. A study in apoE-/- animals showed that deletion of nNOS gene accelerates plaque formation, suggesting an anti-atherogenic effect. So far, there are no studies on the role of nNOS in human atherogenesis. In the present study, the expression of nNOS and its correlation with M1 and M2 macrophages and plaque progression was evaluated in human atherosclerotic CAD. The study was performed in the right coronary artery taken from 34 patients (25 men and 9 women; aged 50 ± 15 years) undergoing heart transplantation. The samples were processed for histology and immunostaining, and based on the stage of atherosclerosis development, they were divided into two groups: early and advanced lesion groups. The results of the present study showed that nNOS was expressed in human coronary artery and that its expression increased with the progression of the atherosclerotic plaque. The expression of nNOS was basically found in macrophages. As the macrophage infiltrate increased, the expression of nNOS also increased. In advanced lesions, all cells that scored positive for nNOS were M1 pro-inflammatory macrophages, whereas in early lesions, less than 3% of cells that scored positive for nNOS were M1 pro-inflammatory macrophages. These data show that in humans, unlike what has been shown in animal models, nNOS appears to have a pro-inflammatory role and may contribute to plaque progression, providing a new perspective on the role of the nNOS enzyme in the development of atherosclerosis.