Role of HIF-1alpha in the regulation ACE and ACE2 expression in hypoxic human pulmonary artery smooth muscle cells.
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 1alpha (HIF-1alpha), a key transcription factor activated during hypoxia, was able to upregulate ACE protein expression under normoxia, whereas knockdown of HIF-1alpha expression in PASMCs inhibited hypoxia-induced ACE upregulation. Furthermore, HIF-1alpha can bind and transactivate the ACE promoter directly. Therefore, we report that ACE is a novel target of HIF-1alpha. 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-1alpha accumulation. Thus HIF-1alpha inhibited ACE2 expression, and the accumulated ANG II catalyzed by ACE is a key mediator in the downregulation of ACE2 by HIF-1alpha. 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-1alpha, 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.
Zhang
Ruifeng
R
Dept. of Respiratory Medicine, Ruijin Hospital, Medical School of Shanghai Jiaotong Univ., No. 197, Second Ruijin Rd., Shanghai 200025, China.
Wu
Yingli
Y
Zhao
Meng
M
Liu
Chuanxu
C
Zhou
Lin
L
Shen
Shaoming
S
Liao
Shihua
S
Yang
Kun
K
Li
Qingyun
Q
Wan
Huanying
H
D000804:Angiotensin II / Q000378:metabolism; D000085962:Angiotensin-Converting Enzyme 2; D015153:Blotting, Western; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D005455:Fluorescent Antibody Technique; D006801:Humans; D006976:Hypertension, Pulmonary / Q000378:metabolism*; D000860:Hypoxia / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000502:physiology*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D007703:Peptidyl-Dipeptidase A / Q000235:genetics / Q000378:metabolism*; D011651:Pulmonary Artery / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic
C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D000804:Angiotensin II; C488034:ACE protein, human; D007703:Peptidyl-Dipeptidase A; C000705307:ACE2 protein, human; D000085962:Angiotensin-Converting Enzyme 2