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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:1760.)
© 2007 American Heart Association, Inc.

Vascular Biology

TNF- Suppresses Prolyl-4-Hydroxylase 1 Expression via the ASK1–JNK–NonO Pathway

Cheng Zhang; Ming-Xiang Zhang; Ying H. Shen; Jared K. Burks; Yun Zhang; Jian Wang; Scott A. LeMaire; Koichi Yoshimura; Hiroki Aoki; Joseph S. Coselli; Xing Li Wang

From the Division of Cardiovascular Surgery (C.Z., M.-X.Z., Y.H.S., J.K.B., J.W., S.A.L., J.S.C., X.L.W.), the Texas Heart Institute at St. Luke’s Episcopal Hospital, and the Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Tex; The Key Laboratory of Cardiovascular Remodeling and Function Research (C.Z., Y.Z.), Chinese Ministry of Education and Chinese Ministry of Public Health, Shandong University, Qilu Hospital, Jinan, Shandong, China; and the Department of Molecular Cardiovascular Biology (K.Y., H.A.), Yamaguchi University School of Medicine, Ube, Japan.

Correspondence to Xing Li Wang, MS BCM 390, One Baylor Plaza, Baylor College of Medicine, Houston, Texas 77030. E-mail xlwang{at}bcm.edu

Background— Inflammation is known to contribute to the pathogenesis of vascular diseases in which arterial wall extracellular matrix (ECM) homeostasis is disrupted. Tumor necrosis factor- (TNF-), a pivotal cytokine that regulates ECM metabolism by increasing degradation and decreasing production of arterial collagens, is associated with vulnerable plaques and aortic aneurysms.

Methods and Results— In the current study, we showed that, when administered in doses of 1 to 100 ng/mL, TNF- dose-dependently downregulated the expression of prolyl-4-hydroxylase I [P4H(I)]—the rate-limiting subunit for the P4H enzyme essential for procollagen hydroxylation, secretion, and deposition in primary human aortic smooth muscle cells (HASMCs). Using a progressive deletion cloning approach, we characterized the TNF-–responsive element (TaRE) in the human P4H(I) promoter and found that a negative regulatory region at the position of –32 to +18bp is responsible for 80% of TNF-–mediated suppression. Using oligonucleotide-based transcription factor pull-down method in which proteins were resolved in 1-D gel electrophoresis and identified using LC-MS/MS, we identified the NonO protein binds this region. When NonO expression silenced with specific siRNA, we found that 70% of the TNF-–mediated P4H suppression was abolished, which appeared to be mediated by the ASK1-JNK pathway.

Conclusions— Our findings define a novel molecular pathway for inflammation associated extracellular matrix dysregulation, which may account for atherosclerotic plaque rupture and aortic aneurysm formation. Further understanding of this pathway may facilitate development of novel therapeutics for vascular diseases.

We showed that TNF-Á dose-dependently downregulated the P4H(I)—the rate-limiting subunit for the P4H enzyme essential for procollagen hydroxylation, secretion, and deposition. Using a progressive deletion cloning approach, we characterized the TNF-Á–responsive element in the P4H(I) promoter and identified the NonO protein may be responsible for the suppressing effect.

Key Words: inflammation • collagen • P4H1TNF- • NonO • JNK • ASK1

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A No-No for NonO and JNK in Extracellular Matrix Homeostasis and Vascular Stability

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