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Hypochlorous acid (HOC1) is a unique oxidant generated by the enzyme myeloperoxidase that contributes to endothelial cell dysfunction and death in atherosclerosis. Since myeloperoxidase localizes with heine oxygenase-1 (HO-1) in and around endothelial cells of atherosclerotic lesions, the present study investigated whether there was an interaction between these two enzymes in vascular endothelium. Treatment of human endothelial cells with the myeloperoxidase product HOC1 stimulated a concentration- and time-dependent increase in HO-1 protein that resulted in a significant rise in carbon monoxide (CO) production. The induction of HO-1 protein was preceded by a prominent increase in HO-1 mRNA and total and nuclear factor-erythroid 2-related factor 2 (Nrf2). In addition, HOC1 induced a significant rise in HO-1 promoter activity that was blocked by mutating the antioxidant response element (ARE) in the promoter or by overexpressing a dominant-negative mutant of Nrf2. The HOCl-mediated induction of Nrf2 or HO-1 was blocked by the glutathione donor N-acetyl-L-cysteine but was unaffected by ascorbic or uric acid. Finally, treatment of endothelial cells with HOCI stimulated mitochondrial dysfunction, caspase-3 activation, and cell death that was potentiated by the HO inhibitor, tin protoporphyrin-IX, or by the knockdown of HO-1, and reversed by the exogenous administration of biliverdin, bilirubin, or CO. These results demonstrate that HOC1 induces HO- 1 gene transcription via the activation of the Nrf2/ARE pathway to counteract HOC1-mediated mitochondrial dysfunction and cell death. The ability of HOC1 to activate HO- 1 gene expression may represent a critical adaptive response to maintain endothelial cell viability at sites of vascular inflammation and atherosclerosis. vascular endothelium; oxidative stress; toxicity; bile pigments; atherosclerosis doi: 10.1152/ajpcell.00536.2008

Two contrasting intrusive suites have been identified from the northern margin of the North China craton: a Late Carboniferous diorite-granodiorite suite mainly made up of quartz diorite, diorite, granodiorite, tonalite, and hornblende gabbro, and a Late Permian-Middle Triassic suite of granitoid intrusions consisting of monzogranite, syenogranite, and quartz monzonite. Plutons from the Late Carboniferous suite exhibit variable Si[O.sub.2] contents and calc-alkaline or high-K calc-alkaline, metaluminous geochemical features. Most have low negative whole-rock [[epison].sub.Nd](T) values (where T is the crystallization age) of -17.1 to -11.5 and zircon [[epsilon].sub.Hf](T) values of-38.3 to -11.2, indicating that they were derived mainly from anatectic melting of the ancient lower crust with some involvement of mantle materials. However, an older pluton in the suite exhibits higher [[epsilon].sub.Nd](T) values of-11.5 to -9.9, Nd model ages of 1.82-1.64 Ga, lower initial [sup.87]Sr/[sup.86]Sr ratios of 0.7046-0.7048, and it contains some zircon grains that are characterized by high negative to positive zircon [[epsilon].sub.Hf](T) values of -8.7 to 1.2, indicating strong involvement of juvenile materials derived from the lithospheric mantle. The Late Carboniferous plutons are interpreted as subduction-related and to have been emplaced in an Andean-style continental-margin arc during the southward subduction of the paleo-Asian oceanic plate beneath the North China craton. Rocks from the Late Permian-Middle Triassic intrusive suite display geochemical signatures ranging from highly fractionated I-type to A-type. They exhibit higher zircon [[epsilon].sub.Hf](T) values of -14.9 to -6.7, whole-rock [[epsilon].sub.Nd] (T) values of -10.6 to -8.8, and younger Hf and Nd model ages than most of the Late Carboniferous plutons, indicating that they could have been produced by extreme fractional crystallization of hybrid magmas resulted from mixing of coeval mantle- and crust-derived melts. They are interpreted as postcollisional/ postorogenic granitoids linked to lithospheric extension and asthenosphere upwelling due to slab break-off and subsequent sinking after final collision and suturing of the Mongolian arc terranes with the North China craton. These two contrasting intrusive suites suggest that the final closure of the paleo-Asian Ocean and collision between the Mongolian arc terranes and the North China eraton occurred during the Late Permian, and these events were followed by postcollisional/ postorogenic extension, large-volume magmatism, and significant continental growth. No significant syncollisional crustal thickening, high-pressure metamorphism, or S-type granitoid magmatism occurred during the collision process. Keywords: North China craton, late Paleozoic-early Mesozoic, active continental margin, petrogenesis, Sr-Nd-Hf isotopes, Central Asian orogenic system.

Author(s): Shan Gao (corresponding author) [1, 2]; Roberta L. Rudnick (corresponding author) [3]; Hong-Ling Yuan [1]; Xiao-Ming Liu [1]; Yong-Sheng Liu [2]; Wen-Liang Xu [4]; Wen-Li Ling [2]; John Ayers [...]