ABSTRACT
Title
Diet, inflammatory profile, and complications of atherosclerotic plaque
Authors
L. Berrino1, P. Golino2
1Department of Experimental Medicine, Pharmacology Division, Second University of Naples, Naples, Italy
2Department of Cardiothoracic Sciences, Division of Cardiology, Second University of Naples, Naples, Italy
1Department of Experimental Medicine, Pharmacology Division, Second University of Naples, Naples, Italy
2Department of Cardiothoracic Sciences, Division of Cardiology, Second University of Naples, Naples, Italy
Abstract
Acute coronary syndromes (ACS) are generally caused by rupture of a plaque within a coronary artery resulting in thrombs formation and myocardial blood flow reduction. Chronic inflammation plays an important role in all stages of atherosclerosis, contributing to the formation, progression, and rupture of atherosclerotic plaques (1). Experimental studies have demonstrated that atherosclerosis is characterized by endothelial activation and dysfunction, lipid accumulation, monocyte infiltration and differentiation, T-cell infiltration and activation, foam cell formation, and fibrosis in the lesion area (2). Several protein mediators, such as chemokines, are produced within atherosclerotic lesions, where they propagate the innate immune response by expressing high levels of proinflammatory cytokines and other macrophage mediators, as matrix metalloproteinases (gelatinase, stromelysin). In particular, matrix metalloproteinases are able to lyse the collagen of the fibrous capsule, promoting desquamative damage of intima. (3)
Recent evidences have also highlighted the potential involvement of mast cells in atherosclerosis. (4). Mast cells release vasoactive small molecules such as histamine and leukotrienes, certain serine proteinases, cofactors involved in growth factors action and angiogenesis. After infiltration, monocytes undergo differentiation into macrophages, which then become foam cells that contain a lipid-laden cytosol. In particular, scavenger receptors are considered to be crucial for lipid accumulation in the macrophage, ultimately leading to foam cell formation (2).
T-cells are frequently found in the atherosclerotic lesion. In particular, T-cells produce IFN-γ which inhibits the proliferation of smooth muscle cells, reduces the synthesis of matrix proteins, and stimulates the production of macrophage metalloproteinases.
However, it has not been clarified yet the molecular mechanism mediating the damage.
Progress in genetics and genomics have heightened interest in defining genetic biomarkers of cardiovascular risk that may open new perspectives in personalized medicine in the future.
Thus, the aim of the present study was to use a genome-wide microarray approach to detect the changes in gene expression (GE) profiling induced by plasma sampled from the coronary circulation of patients with ACS. Methods and results Human coronary artery ECs were stimulated in vitro for 12 hours with plasma obtained from the coronary sinus(CS) and the aorta (Ao) of patients with ACS (n=8), or patients with stable angina (SA, n=4). For each patient, gene expression was evaluated by microarray in ECs exposed to plasma obtained from CS and compared to that of ECs exposed to plasma sampled from Ao. First, we found a conserved pattern of gene expression in both groups of patients (ACS and SA), indicating that plasma from both groups non-specifically induced a pattern of gene expression. In contrast, 539 down-regulated and 9 up-regulated genes were modified exclusively in patients with ACS. Functional and network analyses showed that the down-regulated genes in patient with ACS were associated with pathways of IL-10 signaling, P38 MAPK Signaling, LXR/RXR Signaling, MIF Regulation of innate Immunity, WNT/β-Catenin Signaling, G-Protein Coupled Receptor Signaling, Acute Phase Response Signaling, CCRS Signaling in Macrophages, B Cell Development, FXR/RXR Activation. In contrast, up-regulated genes were not associated with any pathways. Conclusions. Plasma obtained from CS of patients with ACS contains mediators that profoundly modify gene expression profile of ECs; these findings might contribute to unravel the pathophysiology of ACS.
Recent evidences have also highlighted the potential involvement of mast cells in atherosclerosis. (4). Mast cells release vasoactive small molecules such as histamine and leukotrienes, certain serine proteinases, cofactors involved in growth factors action and angiogenesis. After infiltration, monocytes undergo differentiation into macrophages, which then become foam cells that contain a lipid-laden cytosol. In particular, scavenger receptors are considered to be crucial for lipid accumulation in the macrophage, ultimately leading to foam cell formation (2).
T-cells are frequently found in the atherosclerotic lesion. In particular, T-cells produce IFN-γ which inhibits the proliferation of smooth muscle cells, reduces the synthesis of matrix proteins, and stimulates the production of macrophage metalloproteinases.
However, it has not been clarified yet the molecular mechanism mediating the damage.
Progress in genetics and genomics have heightened interest in defining genetic biomarkers of cardiovascular risk that may open new perspectives in personalized medicine in the future.
Thus, the aim of the present study was to use a genome-wide microarray approach to detect the changes in gene expression (GE) profiling induced by plasma sampled from the coronary circulation of patients with ACS. Methods and results Human coronary artery ECs were stimulated in vitro for 12 hours with plasma obtained from the coronary sinus(CS) and the aorta (Ao) of patients with ACS (n=8), or patients with stable angina (SA, n=4). For each patient, gene expression was evaluated by microarray in ECs exposed to plasma obtained from CS and compared to that of ECs exposed to plasma sampled from Ao. First, we found a conserved pattern of gene expression in both groups of patients (ACS and SA), indicating that plasma from both groups non-specifically induced a pattern of gene expression. In contrast, 539 down-regulated and 9 up-regulated genes were modified exclusively in patients with ACS. Functional and network analyses showed that the down-regulated genes in patient with ACS were associated with pathways of IL-10 signaling, P38 MAPK Signaling, LXR/RXR Signaling, MIF Regulation of innate Immunity, WNT/β-Catenin Signaling, G-Protein Coupled Receptor Signaling, Acute Phase Response Signaling, CCRS Signaling in Macrophages, B Cell Development, FXR/RXR Activation. In contrast, up-regulated genes were not associated with any pathways. Conclusions. Plasma obtained from CS of patients with ACS contains mediators that profoundly modify gene expression profile of ECs; these findings might contribute to unravel the pathophysiology of ACS.