At the Incor (Heart Institute) FMUSP (Faculdade de Medicina da USP), research reveals the influence of cardiovascular risk factors on changes in blood vessel cells, linked to the accumulation of fat in diseases such as atherosclerosis.
Genetic analyzes have shown, in an unprecedented way, that cells are uniquely affected by a combination of factors, including high cholesterol and low oxygen concentration in tissues, favoring the appearance of obstructions in blood vessels. The results of the work, which can help to develop therapies that prevent arterial problems, are described in an article published in Scientific Reportsfrom the Nature group.
Atherosclerosis is a complex disease characterized by the accumulation of fat in the walls of the arteries. “The endothelium, a tissue of the blood vessel wall, can initiate this process or be the target of it”, describes professor José Eduardo Krieger, from FMUSP, who participated in the study.
“Initially, there are changes in its functioning, such as a decrease in the capacity to produce vasodilation, which has a great influence on cases of arterial hypertension. Later, structural changes occur.”
“Then, there is the formation of plaques that compromise blood flow to the heart muscle, kidneys, brain and muscles of the upper and lower limbs”, points out the professor. “There are also acute, more tragic events, such as the rupture of plaques and the formation of thrombi that obstruct blood flow to the heart muscle, resulting in myocardial infarction, or stroke, when the brain is affected. “
The work determined the contribution of classical cardiovascular risk factors to endothelial dysfunction, which is a common feature of several cardiovascular diseases, such as atherosclerosis, myocardial infarction and arterial hypertension. “These risk factors are hypoxia, which is the low concentration of oxygen in the tissues, the elevation of cholesterol or inflammatory levels and blood flow disorders”, he points out.
“The study was carried out in vitro, using human endothelial cells, and we evaluated global gene expression changes of about 20,000 genes in our genome in response to risk factor surrogates, individually and in combination.”
The research was done with primary endothelial cells, taken from the vessel wall, from the human coronary artery. “These cells are an important target in atherosclerosis and participate in disorders that affect the heart. The experiments reproduced some of the most important cardiovascular risk factors in a controlled way to quantify their individual and combined effects, as they appear together in most patients affected by cardiovascular diseases”, explains the professor.
“Differences in global endothelial cell gene expression were used to identify gene networks and processes affected by different stimuli generated by risk factors.”
The researchers demonstrated, in a way that has not been described so far, that the combination of stimuli, observed in cardiovascular patients, is not explained only by the sum of the isolated action of each of the risk factors.
“The results of the study make it possible to establish a hierarchy of stimuli, for example, based on the number of differentially expressed genes and the pathways affected by each of the stimuli in isolation in the cells”, says Krieger. “We detected that there are gene networks and biological processes in cells that are uniquely affected by the combination of stimuli, such as proliferative processes [multiplicação de células] and thrombogenic – associated with thrombosis, that is, the formation of obstructions in the vessels, which has not been demonstrated so far.”
According to the professor, the results contribute to a better definition of endothelial dysfunction, identifying the genetic networks and biological processes that are affected by stimuli (risk factors) individually or when combined.
“This hierarchical view of affected gene pathways and biological processes can now be exploited to determine more specific molecular signatures and identify candidate therapeutic targets to prevent or delay the effects of endothelial dysfunction, which is part of most cardiovascular diseases.”
The study is part of a line of research at the Laboratory of Genetics and Molecular Cardiology of Incor, of the HC (Hospital das Clínicas) of FMUSP, which has the collaboration of researchers and partners from various institutions in the country and abroad. THE
The work on endothelial dysfunction had the participation of doctoral student Iguaracy Pinheiro de Souza and researchers Miriam Fonseca-Alaniz, Samantha Teixeira, Mariliza Rodrigues and José Eduardo Krieger.