Cellular and molecular players in the atherosclerotic plaque progression

Abstract

Atherosclerosis initiation and progression is controlled by inflammatory molecular and cellular mediators. Cells of innate immunity, stimulated by various endogenous molecules that have undergone a transformation following an oxidative stress or nonenzymatic glycation processes, activate cells of the adaptive immunity, found at the borders of atheromas. In this way, an immune response against endogenous modified antigens takes place and gives rise to chronic low-level inflammation leading to the slow development of complex atherosclerotic plaques. These lesions will occasionally ulcerate, thus ending with fatal clinical events. Plaque macrophages represent the majority of leukocytes in the atherosclerotic lesions, and their secretory activity, including proinflammatory cytokines and matrix-degrading proteases, may be related to the fragilization of the fibrous cap and then to the rupture of the plaque. A considerable amount of work is currently focused on the identification of locally released proinflammatory factors that influence the evolution of the plaque to an unstable phenotype. A better understanding of these molecular processes may contribute to new treatment strategies. Mediators released by the immune system and associated with the development of carotid atherosclerosis are discussed.

LPS-induced production of TNF-α and IL-6 in mast cells is dependent on p38 but independent of TTP

“…Overexpression of both TNF-α and IL-6 was reported, amongst other syndromes and diseases, to cause cachexia, rheumatoid arthritis, and atherosclerosis [37-40]. Especially for production of TNF-α, intensive research has shown that stability and rate of translation of TNF-α mRNA is tightly regulated by various proteins [5, 12-14, 33].…”

From Lipids to Inflammation

“…9 Cumulatively, this has the effect of recruiting more monocytes into the coronary intima and of attracting smooth muscle cells from the media. 10 Although there has been an emphasis on the critical role of LDL modification before uptake by macrophages, alternative pathways for foam cell formation that do not depend on LDL modification have been described, including uptake of aggregated LDL and fluid phase pinocytosis. 11,12 Although the initial inflammatory response is inherently appropriate, it is ultimately maladaptive in advanced atherosclerosis largely caused by defective inflammation resolution, with persistent recruitment of monocytes that differentiate into proinflammatory macrophages (M1), rather than into alternatively activated macrophages (M2), which promote inflammation resolution.…”

Blunted temporal activity of microvascular perfusion heterogeneity in metabolic syndrome: a new attractor for peripheral vascular disease?

“…For this reason, a detailed understanding of which major contributing processes to an outcome are altered with pathology and the extent for which these are compensated is critical for developing appropriate therapeutic interventions. Failure to elucidate both the key sites of impairment and the compensatory mechanisms, as well as how these impact functional outcomes, has resulted in poorly targeted interventional measures.Although the existing literature contains extensive prior interrogation into the effects of atherosclerotic peripheral vascular disease on perfusion and performance outcomes in multiple model systems as well as the identification of many putative mechanistic contributors to plaque/lesion development (1,9,20,27,30,39), investigation into the impact of nonatherosclerotic peripheral vascular disease (PVD) has received a much more limited investment. Although underrepresented to date, this is an exceedingly important area of investigation, since a growing body of evidence suggests that an increasing number of human subjects are afflicted with the symptomology of PVD in the absence of overt plaque/lesion development (12,19,31,44,45).…”