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

@article{citeulike:5742174, 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) is a key transcription factor activated during hypoxia and was able to upregulate ACE protein expression under normoxia, while 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 homologue of ACE, angiotensin converting enzyme 2 (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 under hypoxia. We conclude that ACE is directly regulated by HIF-1alpha, while ACE2 is regulated in a bidirectional way under hypoxic conditions and may play a protective role during the development of HPH. In sum, these findings contribute to the understanding of the pathogenesis of HPH. Key words: hypoxia-inducible factor 1alpha, angiotensin converting enzyme 2, angiotensin II, hypoxia.}, author = {Zhang, Ruifeng and Wu, Yingli and Zhao, Meng and Liu, Chuanxu and Zhou, Lin and Shen, Shaoming and Liao, Shihua and Yang, Kun and Li, Qingyun and Wan, Huanying}, citeulike-article-id = {5742174}, citeulike-linkout-0 = {http://dx.doi.org/10.1152/ajplung.90415.2008}, citeulike-linkout-1 = {http://view.ncbi.nlm.nih.gov/pubmed/19592460}, citeulike-linkout-2 = {http://www.hubmed.org/display.cgi?uids=19592460}, day = {10}, doi = {10.1152/ajplung.90415.2008}, issn = {1040-0605}, journal = {American journal of physiology. Lung cellular and molecular physiology}, keywords = {ace, ace2, hif, vsmc}, month = {July}, posted-at = {2009-09-08 14:38:50}, priority = {2}, title = {Role of HIF-1{alpha} in the regulation ACE and ACE2 expression in hypoxic human pulmonary artery smooth muscle cells.}, url = {http://dx.doi.org/10.1152/ajplung.90415.2008}, year = {2009} }

TY - JOUR ID - citeulike:5742174 L3 - citeulike-article-id:5742174 N2 - 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) is a key transcription factor activated during hypoxia and was able to upregulate ACE protein expression under normoxia, while 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 homologue of ACE, angiotensin converting enzyme 2 (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 under hypoxia. We conclude that ACE is directly regulated by HIF-1alpha, while ACE2 is regulated in a bidirectional way under hypoxic conditions and may play a protective role during the development of HPH. In sum, these findings contribute to the understanding of the pathogenesis of HPH. Key words: hypoxia-inducible factor 1alpha, angiotensin converting enzyme 2, angiotensin II, hypoxia. JF - American journal of physiology. Lung cellular and molecular physiology SN - 1040-0605 TI - Role of HIF-1{alpha} in the regulation ACE and ACE2 expression in hypoxic human pulmonary artery smooth muscle cells. KW - ace KW - ace2 KW - hif KW - vsmc AU - Zhang, Ruifeng AU - Wu, Yingli AU - Zhao, Meng AU - Liu, Chuanxu AU - Zhou, Lin AU - Shen, Shaoming AU - Liao, Shihua AU - Yang, Kun AU - Li, Qingyun AU - Wan, Huanying PY - 2009/07/10/ UR - http://dx.doi.org/10.1152/ajplung.90415.2008 ER -