The impact of macrophage insulin resistance on advanced atherosclerotic plaque progression

Abstract

Atherothrombotic vascular disease is the major cause of death and disability in obese and diabetic subjects with insulin resistance. Although increased systemic risk factors in the setting of insulin resistance contribute to this problem, it is likely exacerbated by direct effects of insulin resistance on the arterial wall cells that participate in atherosclerosis. A critical process in the progression of subclinical atherosclerotic lesions to clinically relevant lesions is necrotic breakdown of plaques. Plaque necrosis, which is particularly prominent in the lesions of diabetics, is caused by the combination of macrophage apoptosis and defective phagocytic clearance, or efferocytosis, of the apoptotic macrophages. One cause of macrophage apoptosis in advanced plaques is activation of a proapoptotic branch of the unfolded protein response, which is an endoplasmic reticulum stress pathway. Macrophages have a functional insulin receptor signaling pathway, and downregulation of this pathway in the setting insulin resistance enhances unfolded protein response-induced apoptosis. Moreover, other aspects of the obesity/insulin-resistance syndrome may adversely affect efferocytosis. These processes may therefore provide an important mechanistic link among insulin resistance, plaque necrosis, and atherothrombotic vascular disease and suggest novel therapeutic approaches to this expanding health problem.

Figure 1

A CHOP-calcium pathway of ER stress-induced apoptosis in macrophages. A diverse array of ER stress-provoking events, many of which exist in advanced atheromata, trigger the UPR and lead to induction of the downstream effector CHOP. CHOP induces ERO1α, which in turn oxidatively activates IP3R calcium release channels in the ER. IP3R-mediated calcium release begins a pro-apoptotic cascade involving activation of CaMKII by cytosolic calcium and subsequent downstream apoptotic processes, as listed in the figure and as described in the text. In addition, the resulting low level of calcium in the ER lumen likely causes dysfunction of calcium-dependent protein chaperones, which amplifies UPR activation. The central concept is that pro-apoptotic CHOP functions, at least in part, by promoting calcium-induced death as part of a positive feedback cycle (see inset).

Figure 2

Cellular-molecular mechanisms by which macrophage insulin resistance promotes ER stress-induced macrophage apoptosis and advanced plaque progression. At least three pro-apoptotic processes are enhanced in ER stressed macrophages: (1) ER stress normally activates a compensatory MEK-ERK-SERCA pathway to lower cytoplasmic calcium and replenish ER lumenal stores. This pathway is blocked in the setting of insulin resistance, leading to enhanced activation of calcium-mediated apoptotic pathways (increased cytosolic calcium) and further UPR-CHOP activation (decreased ER lumenal calcium); (2) pattern recognition receptors like scavenger receptors are up-regulated in insulin-resistant macrophages, and, when activated, are synergistic with ER stress in inducing apoptosis (“2^nd hit” concept); (3) Increased nuclear FoxO in insulin-resistant macrophages induces IκBε, thereby suppressing a compensatory NF-κB cell-survival pathway. In addition to these pro-apoptotic processes, increased levels of saturated fatty acids in the setting obesity compromise the ability of macrophages to engulf apoptotic cells. Apoptotic cells that are not efficiently cleared become secondarily necrotic and, over time, accumulate into necrotic cores in advanced plaques. These necrotic cores, which are particularly large in diabetic atheromata, are thought to contribute to plaque disruption. See text for details.