Endoplasmic reticulum stress and atherosclerosis

Abstract

Atherosclerosis and related cardiovascular diseases represent one of the greatest threats to human health worldwide. Despite important progress in prevention and treatment, these conditions still account for one third of all deaths annually. Often presented together with obesity, insulin resistance and type 2 diabetes, these chronic diseases are strongly influenced by pathways that lie at the interface of chronic inflammation and nutrient metabolism. Here I discuss recent advances in the study of endoplasmic reticulum stress as one mechanism that links immune response with nutrient sensing in the pathogenesis of atherosclerosis and its complications.

Figure 1

Canonical unfolded protein response. The unfolded protein response (UPR) results in the inhibition of translation, facilitated protein degradation and production of ER chaperones and other molecules that restore the ER folding environment. These activities are signaled through three UPR sensors—PERK, IRE1a and ATF6—that mediate the canonical response pathways. PERK phosphorylates eIF2a to attenuate general protein translation. It can also regulate the activity of several transcription factors such as ATF4, ATF3 and nuclear factor E2–related factor-2 (Nrf2). Upon autophosphorylation, the RNase activity of IRE1a results in the production of spliced and active XBP-1, leading to the expression and production of ER chaperones and components of the ER-associated degradation (ERAD) process. ATF6 moves to the Golgi apparatus, where it is proteolytically processed to generate an active transcription factor (ATF6(N)) that stimulates the expression of chaperones and XBP-1. There may be additional and unknown aspects of UPR, especially related to the sensing of nutrients and mediation of metabolic adaptations. ERO1, endoplasmic reticulum oxidoreduction-1.

Figure 2

Macrophage ER stress in inflammation and apoptosis. In atherosclerosis and obesity, excess lipids such as saturated fatty acids or free cholesterol, homocysteinemia, hypoxic stress and other inflammatory and toxic signals can stimulate ER stress and activate the UPR. An upstream mechanism that links these toxic lipids to ER stress involves the action of lipid chaperones through inhibition of LXRα and suppression of a protective lipogenic program that enriches the cells in monounsaturated fatty acids such as palmitoleate (C16:1n7-palmitoleate). Once the cells are committed to death as a result of unresolved ER stress, several well-characterized mechanisms that involve the PERK and IRE1 branches of the UPR act to mediate macrophage apoptosis. These involve association of Bax/Bak with IRE1, activation of JNK, activation of calmodulin kinase II (CaMK-II) owing to abnormal Ca²⁺ fluxes, and a PERK-mediated increase in CHOP levels and activity. Other factors such as insulin resistance, production of reactive oxygen species (ROS) and nitric oxide (NO) production could also contribute to the apoptotic and inflammatory responses. The apoptotic and inflammatory responses may also involve activation of p38 and STAT1, although the links to specific UPR sensors are not entirely clear. The role of the ATF6 branch of the UPR in macrophage function or atherosclerosis remains unknown. p38 MAPK, p38 mitogen-activated kinase. SCD-1, stearoyl-CoA desturase-1.