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

Abstract

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.

Cell cycle dependence of ACE-2 explains downregulation in idiopathic pulmonary fibrosis

“…In cultured human pulmonary artery smooth muscle cells exposed to hypoxia in vitro, ACE-2 mRNA and protein were transiently upregulated in a manner dependent on the transcription factor hypoxia-inducible factor-1a [31]. However, ACE-2 was downregulated in these cells by ANGII in a manner inhibitable by antagonists of the AT1 receptor but not by AT2 receptor antagonists.…”

Angiotensin II regulates ACE and ACE2 in neurons through p38 mitogen-activated protein kinase and extracellular signal-regulated kinase 1/2 signaling

“…Our laboratory has shown that several transcription factors, including activator protein-1, NF-B, and cAMP responsive element-binding protein, are involved in the regulation of AT 1 R expression in response to ANG II (20, 22; unpublished observations inducible factor 1␣ has been shown to inhibit ACE2 and promote ACE expression in pulmonary artery smooth muscle cells during hypoxic pulmonary hypertension (41). A study by Cardinale et al (2) showed that chronic subcutaneous infusion of ANG II resulted in an increase in ACE and a decrease in ACE2 expression in the PVN, which were normalized by inhibition of NF-B.…”

Ontogeny of angiotensin-converting enzyme 2

“…The factors regulating tissue-specific developmental expression of ACE2 remain to be determined. One potential mechanism may involve transcriptional repression of ACE2 by hypoxia-inducible factor 1α or activation by hepatocyte nuclear factor 1β (29,30). In addition, ACE2 expression can be induced by retinoic acid (vitamin A).…”