Nitric oxide (NO) is a multifunctional biomolecule involved in a variety of physiological and pathological processes, including regulation of blood vessel dilatation and anti-arteriosclerotic effects. However, a large amount of NO is toxic to the host and causes several diseases such as apoptosis, septic shock, and diabetes mellitus. Inducible-form NO synthase is induced in inflammatory diseases, including insulitis and arteriosclerosis. Endoplasmic reticulum (ER) stress pathway was first identified as a cellular response pathway induced by the accumulation of unfolded proteins in ER to preserve ER functions. Later it was found that ER stress pathway is also activated by various cellular stresses to protect cells, but when stresses are severe, apoptosis is induced to remove damaged cells. It is reported that NO and reactive oxygen species disturb ER functions, then ER stress-mediated apoptosis pathway is activated. CHOP/GADD153, which belongs to C/EBP transcription factor family, is induced in this proces...
Objective—To elucidate whether and how the endoplasmic reticulum (ER) stress-C/EBP homologous protein (CHOP) pathway in macrophages is involved in the rupture of atherosclerotic plaques. Methods and Results—Increases in macrophage-derived foam cell death in coronary atherosclerotic plaques cause the plaque to become vulnerable, thus resulting in acute coronary syndrome. The ER stress–CHOP/growth arrest and DNA damage-inducible gene-153 (GADD153) pathway is induced in the macrophage-derived cells in atherosclerotic lesions and is involved in plaque formation. However, the role of CHOP in the final stage of atherosclerosis has not been fully elucidated. Many CHOP-expressing macrophages showed apoptosis in advanced ruptured atherosclerotic lesions in wild-type mice, whereas few apoptotic cells were observed in Chop−/− mice. The rupture of atherosclerotic plaques was significantly reduced in high cholesterol–fed Chop−/−/Apoe−/− mice compared with Chop+/+/Apoe−/− mice. Furthermore, using mice that underwent bo...
Objective—To investigate whether and how the endoplasmic reticulum (ER) stress–induced, CCAAT/enhancer-binding protein-homologous protein (CHOP)-mediated pathway regulates myocardial ischemia/reperfusion injury. Methods and Results—Wild-type and chop-deficient mice underwent 50 minutes of left coronary artery occlusion followed by reperfusion. Expression of chop and spliced x-box binding protein-1 (sxbp1) mRNA was rapidly and significantly increased in reperfused myocardium of wild-type mice. chop-deficient mice exhibited markedly reduced injury size after reperfusion compared with wild-type mice, accompanied by a decreasing number of terminal deoxynucleotidyl transferase dUTP nick-end labeling–positive cardiomyocytes. Interestingly, myocardial inflammation, as assessed by expression of inflammatory cytokines and chemokines and numbers of infiltrated inflammatory cells, was also attenuated in chop-deficient mice. Moreover, expression of interleukin-6 mRNA in response to lipopolysaccharide was enhanced by ...
