Reduced Apoptosis and Plaque Necrosis in Advanced Atherosclerotic Lesions of Apoe−/− and Ldlr−/− Mice Lacking CHOP

Abstract

SUMMARY Endoplasmic reticulum (ER) stress is a hallmark of advanced atherosclerosis, but its causative role in plaque progression is unknown. In-vitro studies have implicated the ER stress effector CHOP in macrophage apoptosis, a process involved in plaque necrosis in advanced atheromata. To test the effect of CHOP deficiency in vivo, aortic root lesions of fat-fed Chop+/+;Apoe−/− and Chop−/−;Apoe−/− mice were analyzed for size and morphology. Despite similar plasma lipoproteins, lesion area was 35% smaller in Chop−/−;Apoe−/− mice. Most importantly, plaque necrosis was reduced by ~50% and lesional apoptosis by 35% in the CHOP-deficient mice. Similar results were found in fat-fed Chop−/−;Ldlr−/− vs. Chop+/+;Ldlr−/− mice. Thus, CHOP promotes plaque growth, apoptosis, and plaque necrosis in fat-fed Apoe−/− and Ldlr−/− mice. These data provide direct evidence for a causal link between the ER stress effector CHOP and plaque necrosis and suggest that interventions weakening this arm of the UPR may lessen plaque progression.

HDLs inhibit endoplasmic reticulum stress and autophagic response induced by oxidized LDLs

“…33 It's implication in atherosclerosis has been recently reported in mice double knock down for CHOP and ApoE, which exhibit a lower extent of atherosclerotic lesions, and less necrotic regions within the plaque. 34 These data suggest that ER stress and particularly CHOP, may promote cell death within the vascular wall and atherosclerosis. Interestingly, HMEC-1 cells silenced for CHOP by siRNA, or fibroblasts issued from CHOP-/-mice, 32 were partly resistant to the cytotoxic effect of oxLDLs, which supports a role for ER stress and CHOP in oxLDLs-mediated apoptosis, in agreement with Tabas et al 34 Moreover, we show that HDLs inhibit the phosphorylation of JNK induced by oxLDLs, which in our system is activated by IRE1a, and is involved in ER stress-dependent apoptosis 9, via the JNK proapoptotic pathway, as reported.…”

“…34 These data suggest that ER stress and particularly CHOP, may promote cell death within the vascular wall and atherosclerosis. Interestingly, HMEC-1 cells silenced for CHOP by siRNA, or fibroblasts issued from CHOP-/-mice, 32 were partly resistant to the cytotoxic effect of oxLDLs, which supports a role for ER stress and CHOP in oxLDLs-mediated apoptosis, in agreement with Tabas et al 34 Moreover, we show that HDLs inhibit the phosphorylation of JNK induced by oxLDLs, which in our system is activated by IRE1a, and is involved in ER stress-dependent apoptosis 9, via the JNK proapoptotic pathway, as reported. 40 The effect of oxLDLs and HDLs on ER stress-induced apoptosis is also favoured by caspase-12 processing that occurs upon oxLDLs stimulation and which is inhibited by HDLs in murine 25 However, the precise role of caspase-12 in human is still undefined and need further investigation as human caspase-12 gene encodes an aberrant caspase.…”

Targeting IRE1 with small molecules counteracts progression of atherosclerosis

“…Thus, the reduction in plaque size that we observed in our study is likely to result from IRE1 inhibitor-mediated antiinflammatory changes and not to result from the product of changes in lipid metabolism. Although we have seen important gains in mitigating atherosclerosis by pharmacologically targeting IRE1 in our experimental models, it is important to note that the other UPR branches, particularly the PERK-CHOP branch, are also induced as atherosclerosis progresses and seem to be instrumental for macrophage apoptosis (5,11). Previous studies focusing on the engagement of apoptotic pathways initiated by the UPR (such as those mediated by CHOP and JNK) showed that mice deficient for these apoptotic effectors are protected from atherosclerosis (5,(11)(12)(13).…”

“…Although we have seen important gains in mitigating atherosclerosis by pharmacologically targeting IRE1 in our experimental models, it is important to note that the other UPR branches, particularly the PERK-CHOP branch, are also induced as atherosclerosis progresses and seem to be instrumental for macrophage apoptosis (5,11). Previous studies focusing on the engagement of apoptotic pathways initiated by the UPR (such as those mediated by CHOP and JNK) showed that mice deficient for these apoptotic effectors are protected from atherosclerosis (5,(11)(12)(13). Independent of CHOP or JNK engagement, here, we found that modulating IRE1 signaling in vivo with small molecule IRE1 inhibitors modifies a different branch of UPR signaling that impinges on metaflammation and alters the course of atherosclerosis.…”

“…For example, inhibiting the apoptotic signaling downstream of ER stress through genetic deletion of the proapoptotic transcription factor CCAAT box binding enhancer homologous protein (CHOP) or the signal transducer c-jun N-terminal kinase (JNK) blocks atherosclerosis progression (5,(11)(12)(13). Moreover, modulation of ER stress by using chemical chaperones alleviates atherosclerosis, further supporting the idea that therapeutic modulation of ER function is a promising avenue to combat atherosclerosis (14)(15)(16).…”