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Freeing the arteries

Researchers create a bio-marker that detects the formation of fatty depositsin arteries and discover in plasma a potent vasodilator

Two discoveries by a group from the University of São Paulo (USP) are opening up new possibilities for the prevention and combat of atherosclerosis, an illness that blocks blood circulation in the of the large and medium arteries, and can bring about cerebral hemorrhages and heart attacks. During four years of work, the team from the Pharmaceutical Sciences School (FCF), coordinated by Dulcinéia Saes Parra Abdalla, first developed a marker that makes the diagnosis of the infirmity easier, since it identifies the part of a lipoprotein – named negative LDL – which sets off the atherosclerosis.

Within another part of the same project, the existence in human plasma of two structures that work as reservoirs for nitric oxide – a powerful vasodilator -, has been proven, as can be attested to in the article published in this month’s edition of the magazine Biochemistry. Should these substances present the same behavior observed in the laboratory, they could be used in the treatment of atherosclerosis and in the prevention of strokes and heart attacks.

The two advances involve one of the most serious Public Health problems: it is calculated that atherosclerosis affects close to 10% of the world’s population over fifty years of age, above all men. At an advanced age, hyperlipidemia (a high level of fat in the blood), hypertension, diabetes, smoking, lack of exercises and family hereditary are risk factors for developing illnesses.

Mistaken marker
The work began during the 90s and involved the challenge of studying the lipoproteins, spherical particles made up of proteins on their surface and fats (lipids) within. The lipoproteins form in various locations of the organism and assume distinctive functions. When they originate in the blood, they are called LDL (proteins of low density, with a low concentration of triglycerides and a high level of cholesterol) and they distribute cholesterol to the peripheral tissues.

However, the negative LDL – formed during oxidation processes – is responsible for artherogenesis (formation of arterial lesions), that brings on atherosclerosis. This occurs, among other factors, because immunological cells called macrophages capture particles of LDL and form complete fatty cells, which accumulate close to the walls of the arteries, progressively blocking the circulation of the blood.

Although the mechanisms of the deflagration were reasonably well known, there was a stone on the way. Due to the complexity of the lipoproteins, the markers up until that moment were misleading: they identified only the total amount of LDL, and not the negative fraction, which did not allow for the confirmation that one was dealing with a process of atherosclerosis.

Non-invasive method
Dulcinéia’s team developed, as a consequence, tests to consolidate and to validate an explicit marker: they made in the laboratory a monoclonal antibody – produced by the clones of a cell – which points to the exclusive presence of negative LDL. “Currently the diagnosis is done by way of examinations such as cineangiocoronary graph, in which a catheter is introduced into the arteries, and the injected contrast allows for the visualization of the coronaries. We managed to obtain a non-invasive form of evaluating the illness”, the researcher says. By being a more simple method, sensitive and non-invasive, she hopes that it will turn itself into a routine procedure carried out along with a medical request such as blood examinations.

After the completion of the study, Dulcinéia confirmed that the marker is efficient enough to detect the presence and the quantity of negative LDL, both in the blood stream and in the lesions already presented in the arteries: “It’s adequate to inform the probability of the development of the illness and the damages that it has already caused. It carries this out in a simple manner, which can be applied on a widened scale”.

The next stage will be to apply the test in clinical and intervention studies that involves human beings. For the researcher, the work is a major advance in the evaluation of atherosclerosis, and the marker will help to define the treatment for each case.The team has sent off to the National Institute of Intellectual Property (INPI) a request for the registration of a patent that will cover the monoclonal antibody and its possible commercial and therapeutic applications. During the studies, the USP group had the collaboration of Alex Sevanian, of the University of Southern California, researchers from the Universdad de la Republica in Montevideo, and from the Chemistry Institute of USP.

Vital pollutant
In another part of the work, the researchers demonstrated that, for the first time, structures present in human plasma could be reservoirs of potent vasodilators synthesized by the organism itself, the compound nitric dioxide – elected during 1992 as the molecule of the year by the magazine Science. “One of the most surprising discoveries of the last decade”, emphasizes the researcher, “was the demonstration that pollutant gases such as nitric oxide (NO) and nitrogen dioxide (NO2) are produced in human organisms” Research confirms that, besides being an importance signaler in the cardiovascular system, nitrogen oxide is synthesized in nerve cells and diffuses rapidly, activating neighboring cells. “This gas could modulate many organic functions, from the regulating of hormonal functions to behavior”.

Studies carried out abroad have proven that patients with atherosclerosis have less capacity for vasodilatation. There has been a strong suspicion that this was occurring because the nitric dioxide reacted with other targets and not with the arteries. One of these locations for reaction could be the total LDL itself.

Based on these possibilities and beginning with a fatty acid – linoleic acid -, the group synthesized in the laboratory an experimental model that confirmed: when is enters into the LDL, the nitric oxide originates two products – the nitrated lipids and the nitrosilades – which function as reservoirs of the vasodilator. With this reference in hand, the team again turned their attention to the human plasma and verified that the two products also show themselves in it. “The great doubt is to know if, in the blood, they also act as reservoirs of nitric oxide, since that which occurs in the laboratory is not always repeated in practice. This is one of the next steps that we intend to take”, reveals Dulcinéia.

If this hypothesis is confirmed, the doctors will have at their disposition a new possibility of therapy: the two products, which are atoxic, could release the nitric xide which they accumulate. “In this manner, they could alleviate the symptoms of the illness and avoid the risk of ischemias and heart attacks”, underlines the researcher.

The project
Possible Connections between Hypertension and Hypercholesterolemia, in Relation to atherosclerosis: Means for the Inactivation of Nitric Oxide and the Oxidation of Lipoproteins (nº 97/05090-3); Modality Thematic project; Coordinator Dulcinéia Saes Parra Abdalla – USP; Investment R$ 1,028,474.02