Molecular Regulation of Atherosclerosis Regression - Renewal

ABSTRACT Coronary plaques begin their progression in childhood, making their reversal an important clinical goal in adulthood. The understanding of mechanisms underlying atherosclerosis regression has been understudied compared to plaque progression. Atherosclerosis represents a failure to resolve the maladaptive immune response that maintains plaque growth through the accumulation of pro-inflammatory immune cells. The central inflammatory cell in the plaque is the macrophage (Mø) in the activated state. We previously showed that plaque regression in mouse models is characterized by the enrichment of Møs in the inflammation resolving state (which we will refer to as proR-Møs). We have recently shown that these proR-Møs are required for regression. We also have observed in regressing plaques increased numbers of inflammation dampening CD4+ regulatory T cells (Tregs), which prevent the expansion of effector T cells and support proR-Mø functions. Furthermore, our results point to Wnt-signaling and chemokine receptor CCR7 as key pathways associated with a pro-resolving environment. We hypothesize that all of these factors play important roles in the reprogramming of the plaque inflammatory milieu to enable inflammation tissue repair in the artery wall and thereby promote atherosclerosis regression. The development of novel therapies for atherosclerosis must also take into account “real world” clinical issues. Accumulating data now show that the majority of treated patients intermittently adhere to statins, which increases their CAD risk. We hypothesize that epigenetic reprogramming of macrophages and their precursors by IH through trained immunity mediates these adverse effects on atherosclerosis, further hindering inflammation resolution and rendering plaques susceptible to accelerated disease and refractory to regression. We have developed the following specific aims to investigate the factors and pathways that drive or hinder inflammation resolution and plaque remodeling during atherosclerosis regression: Aim 1: To study the regulation of the inflammation-resolving properties of plaque Møs by Wnt-signaling. Aim 2: To determine the role of CCR7 in the resolution of atherosclerotic inflammation and plaque regression. Aim 3: To establish the mechanistic basis for increased coronary artery disease risk in patients with intermittent statin adherence. In summary, this proposal represents an exciting opportunity to continue to combine our collective expertises to address crucial gaps in our knowledge of the resolution of inflammation in atherosclerosis.