Atherosclerosis Signaling


Pathway Description

Atherosclerosis is a condition in which artery walls thicken as the result of a build-up of fatty materials such as cholesterol. Atherosclerosis is now considered a specific form of a chronic inflammatory process resulting from interactions between plasma lipoproteins, cells [monocytes/macrophages, endothelial cells (EC), smooth muscle cells (SMC) and T-lymphocytes], and the extracellular matrix of the arterial wall. Atherogenic lipoproteins such as oxidized-LDL, VLDL and Lp(a) play an initiating role in this disease by up-regulating adhesion molecules such as ICAM-1 and VCAM-1 on endothelial cell surfaces. This allows the adhesion of monocytes to ECs. Monocytes migrate into the intima of the blood vessel where they differentiate into macrophages under the influence of M-CSF.

Macrophages take up ox-LDL through scavenger receptors on their cell surface to form foam cells. Such lipid laden foam cells in the intima form what is called the "fatty streak". Foam cells secrete pro-inflammatory cytokines such as IL-1, IL-6 , IL-8, as well as MMPs and tissue factor(TF). This in turn amplifies the local inflammatory response and stimulates SMC proliferation and initial migration toward the lesion. These are the origins of the formation of the "stable plaque". A stable plaque is characterized by a large lipid core covered by a thick fibromuscular cap with SMCs and ECM.

Under conditions of chronic inflammation, a stable plaque begins to shift towards an unstable/vulnerable plaque. This transition is accompanied by further accumulation of macrophages and T-lymphocytes. CD40L on T-lymphocytes binds to CD40 on macrophages increasing the expression of TF and MMPs in macrophages. There is a shift towards a Th1 pattern. Mast cells secrete enzymes that activate MMPs. Increasing production and activation of MMPs leads to degradation of the ECM. SMCs are also inhibited, further reducing collagen in the matrix. All these events lead to thinning of the fibrous cap which eventually ruptures. Vulnerable plaque rupture results in thrombosis and possible myocardial infarction.