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This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: 297/4/L631    most recent 90415.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Zhang, R. Articles by Wan, H. PubMed PubMed Citation Articles by Zhang, R. Articles by Wan, H.

Role of HIF-1 in the regulation ACE and ACE2 expression in hypoxic human pulmonary artery smooth muscle cells

Department of ¹Respiratory Medicine, Ruijin Hospital, Medical School of Shanghai Jiaotong University, Shanghai; Department of ⁴Gastroenterology, Ruijin Hospital, Medical School of Shanghai Jiaotong University, Shanghai;; ³Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, Shanghai; and ; ²Department of Respiratory Medicine, Sir Run Run Shaw Hospital, Medical School of Zhejiang University, Hangzhou, China

Submitted 4 August 2008 ; accepted in final form 3 July 2009

Angiotensin-converting enzyme (ACE) enhances the proliferation and migration of pulmonary artery smooth muscle cells (PASMCs), which contribute to the pathogenesis of hypoxic pulmonary hypertension (HPH). Previous reports have demonstrated that hypoxia upregulates ACE expression, but the underlying mechanism is unknown. Here, we found that ACE is persistently upregulated in PASMCs on the transcriptional level during hypoxia. Hypoxia-inducible factor 1 (HIF-1), a key transcription factor activated during hypoxia, was able to upregulate ACE protein expression under normoxia, whereas knockdown of HIF-1 expression in PASMCs inhibited hypoxia-induced ACE upregulation. Furthermore, HIF-1 can bind and transactivate the ACE promoter directly. Therefore, we report that ACE is a novel target of HIF-1. Recently, a homolog of ACE, ACE2, was reported to counterbalance the function of ACE. In contrast to ACE, we found that ACE2 mRNA and protein levels increased during the early stages of hypoxia and decreased to near-baseline levels at the later stages after HIF-1 accumulation. Thus HIF-1 inhibited ACE2 expression, and the accumulated ANG II catalyzed by ACE is a key mediator in the downregulation of ACE2 by HIF-1. Moreover, a reduction of ACE2 expression in PASMCs by RNA interference was accompanied by significantly enhanced proliferation and migration during hypoxia. We conclude that ACE is directly regulated by HIF-1, whereas ACE2 is regulated in a bidirectional way during hypoxia and may play a protective role during the development of HPH. In sum, these findings contribute to the understanding of the pathogenesis of HPH.

hypoxia-inducible factor 1; angiotensin-converting enzyme 2; angiotensin II; hypoxia