Abstract 405: Deficiency of p38α MAPK in Macrophages Promotes Apoptosis and Plaque Necrosis in Advanced Murine Atherosclerotic Lesions
Endoplasmic reticulum (ER) stress occurs in macrophage-rich areas of advanced atheroscle-rotic lesions and contributes to macrophage apoptosis and subsequent plaque necrosis. Therefore, signaling pathways that alter ER stress-induced apoptosis may affect the development of advanced atherosclerosis. Here we show that Western diet-fed Apoe−/− mice deficient in macrophage p38α MAPK have a marked increase in apoptosis and plaque necrosis. We found a significant increase in the mean necrotic area in the p38α-deficient lesions (46,700 μm2 versus 18,965 μm2 in the control mice, p < 0.008). Quantification of the data revealed an approximate 51% increase in the percent of apoptotic cells in the p38α-deficient lesions. The macrophage-p38α-deficient lesions also exhibited a 30% decrease in collagen content and a 40% decrease in fibrous cap thickness. Consistent with our in vivo data, we found that ER stress-induced apoptosis in cultured macrophages was markedly accelerated under conditions of p38 inhibition, and this effect was further enhanced in the setting of insulin resistance. Mechanistic experiments revealed that p38 inhibition causes suppression of the pro-survival Akt pathway in vitro and in vivo. We found that inhibition of Akt with LY294002 enhances apoptosis under conditions of ER stress. Furthermore, expression of a constitutively active Akt, myristoylated-Akt, blocked the enhancement of apoptosis that occurred with p38 inhibition, but did not inhibit apoptosis induced by ER stress itself. In view of clinical trials exploring the use of p38 inhibitors in inflammatory diseases, our results raise the possibility that these drugs may promote plaque progression in subjects with advanced atherosclerotic lesions.
This research has received full or partial funding support from the American Heart Association, AHA Founders Affiliate (Connecticut, Maine, Massachusetts, New Hampshire, New Jersey, New York, Rhode Island, Vermont).