Hypoxia induces expression of connective tissue growth factor in scleroderma skin fibroblasts

Abstract

SummaryConnective tissue growth factor (CTGF) plays a role in the fibrotic process of systemic sclerosis (SSc). Because hypoxia is associated with fibrosis in several profibrogenic conditions, we investigated whether CTGF expression in SSc fibroblasts is regulated by hypoxia. Dermal fibroblasts from patients with SSc and healthy controls were cultured in the presence of hypoxia or cobalt chloride (CoCl2), a chemical inducer of hypoxia-inducible factor (HIF)-1a. Expression of CTGF was evaluated by Northern and Western blot analyses. Dermal fibroblasts exposed to hypoxia (1% O2) or CoCl2 (1-100 mM) enhanced expression of CTGF mRNA. Skin fibroblasts transfected with HIF-1a showed the increased levels of CTGF protein and mRNA, as well as nuclear staining of HIF-1a, which was enhanced further by treatment of CoCl2. Simultaneous treatment of CoCl2 and transforming growth factor (TGF)-b additively increased CTGF mRNA in dermal fibroblasts. Interferon-g inhibited the TGF-b-induced CTGF mRNA expression dose-dependently in dermal fibroblasts, but they failed to hamper the CoCl2-induced CTGF mRNA expression. In addition, CoCl2 treatment increased nuclear factor (NF)-kB binding activity for CTGF mRNA, while decreasing IkBa expression in dermal fibroblasts. Our data suggest that hypoxia, caused possibly by microvascular alterations, up-regulates CTGF expression through the activation of HIF-1a in dermal fibroblasts of SSc patients, and thereby contributes to the progression of skin fibrosis.

Role for Staphylococci in Misguided Thrombus Resolution of Chronic Thromboembolic Pulmonary Hypertension

“…38 Hypoxia-inducible factor 1 that is activated on bacterial infection 39 induces CTGF expression, possibly via a hypoxia-responsive element in the CTGF promotor. 40 Peptidoglycan from S aureus causes rapid release of tumor necrosis factor (TNF)-␣ and other inflammatory cytokines resulting in TGF-␤ induction. 41 Similarly, S aureus protein A, a highly expressed surface component, can mimic TNF-␣ to activate its receptor and initiate subsequent proinflammatory 42 and profibrotic signaling.…”

Microvascular destruction identifies murine allografts that cannot be rescued from airway fibrosis

“…How hypoxia and ischemia may incite fibrosis is not established. In vitro studies have demonstrated profibrotic phenotypic change of fibroblasts in response to hypoxia (34)(35)(36). Epithelial and endothelial cells can undergo mesenchymal transition under ischemia to become another source of activated fibroblasts (37).…”

Coagulation and the Vessel Wall in Pulmonary Embolism

“…97 Furthermore, local hypoxia may upregulate PAI-1 expression 103 in the remodeling/organization regions within the thrombi and induce expression of connective-tissue growth factor (CTGF) via a hypoxia-responsive element in the CTGF promoter. 104 Recent data have shown that genetic ablation of the BMPR2 gene in pulmonary endothelium induces in situ thrombosis, suggesting a role for the TGF-β pathway in thrombus organization. 105 …”