Macrophage deficiency of p38α MAPK promotes apoptosis and plaque necrosis in advanced atherosclerotic lesions in mice

Abstract

ER stress occurs in macrophage-rich areas of advanced atherosclerotic lesions and contributes to macrophage apoptosis and subsequent plaque necrosis. Therefore, signaling pathways that alter ER stress-induced apoptosis may affect advanced atherosclerosis. Here we placed Apoe -/-mice deficient in macrophage p38α MAPK on a Western diet and found that they had a marked increase in macrophage apoptosis and plaque necrosis. The macrophage p38α-deficient lesions also exhibited a significant reduction in collagen content and a marked thinning of the fibrous cap, which suggests that plaque progression was advanced in these mice. Consistent with our in vivo data, we found that ER stress-induced apoptosis in cultured primary mouse macrophages was markedly accelerated under conditions of p38 inhibition. Pharmacological inhibition or genetic ablation of p38 suppressed activation of Akt in cultured macrophages and in atherosclerotic lesions. In addition, inhibition of Akt enhanced ER stress-induced macrophage apoptosis, and expression of a constitutively active myristoylated Akt blocked the enhancement of ER stress-induced apoptosis that occurred with p38 inhibition in cultured cells. Our results demonstrate that p38α MAPK may play a critical role in suppressing ER stress-induced macrophage apoptosis in vitro and advanced lesional macrophage apoptosis in vivo.

Calcium/calmodulin-dependent protein kinase II links ER stress with Fas and mitochondrial apoptosis pathways

“…This concept fits well with our overall concept that individual proapoptotic hits are subthreshold (15) and that multiple subthreshold hits - in this case, all 3 of the CaMKII pathways depicted in Figure 10 - are necessary for apoptosis. In addition to the activation of multiple subthreshold proapoptotic pathways, the multihit concept also involves suppression of compensatory cell survival pathways, such as those involving IFN-β and Akt-p38α, that are often induced in parallel with UPR activation (23,60).…”

The Endoplasmic Reticulum Stress Sensor, ATF6α, Protects against Neurotoxin-induced Dopaminergic Neuronal Death

“…Previous studies reported that p38MAPK plays a critical role in suppressing ER stress-induced macrophage apoptosis in vitro and advanced lesional macrophage apoptosis in vivo (35). On the contrary, p38MAPK also has a pro-apoptotic role in maintaining homeostasis under various stresses.…”

Molecular Biology of Atherosclerosis

“…While the increase in lesion size was not significant, there was certainly no decrease as might have been expected. Instead, there was marked increase in apoptotic markers, necrotic areas, a decrease in collagen deposition, and thinning of the fibrous cap (1583). Uptake of apoptotic cells by macrophages (efferocytosis) triggers an antiinflammatory release of IL-10 and TGF␤ dependent on p38 (473).…”

“…Other examples of a need for balanced, modest activation have been reported, as in the limited oxidative stress required to activate Nrf2. Some NF-B pathway activity is protective (as macrophage-specific IKK2 KO caused increased atherosclerosis) and the absence of the MAPK p38 in macrophages greatly increased apoptosis and necrosis with accelerated atherosclerosis (1583). This may also explain why KO of MAPK phosphatase 1 (MKP-1), which inhibits p38, actually decreased plaque size (see TABLE 1).…”