{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T16:21:56Z","timestamp":1792686116475,"version":"4.5.0"},"reference-count":63,"publisher":"American Physiological Society","issue":"3","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Lung Cellular and Molecular Physiology"],"published-print":{"date-parts":[[2012,8,1]]},"abstract":"<jats:p> Apoptotic cell death is essential for mammalian development and tissue homeostasis. Dysregulation of apoptosis has been identified in pathologies including in pulmonary fibrotic remodeling. We previously reported that a key proapoptotic factor in fibrosis, angiotensin II (Ang II), mediates apoptosis in primary pulmonary artery endothelial cells (PAEC) via the AT<jats:sub>2<\/jats:sub> receptor and requires activation of AMP-regulated protein kinase (AMPK). We now demonstrate that Ang II induces E2F1 transcription factor binding to and activation of the promoter for the Bcl-2 homology 3 (BH3)-only protein Bim. In PAEC, Ang II treatment induced cyclin-dependent kinase 4 (Cdk4)-mediated hyperphosphorylation of retinoblastoma protein (Rb) and its disassociation from E2F1, a key step in facilitating E2F1-directed transcriptional activity. Indeed, ectopic expression of a dominant negative Cdk4 mutant inhibited Ang II-mediated hyperphosphorylation of Rb and Bim promoter activation. Our data also show that the \u03b2-subunit of AMPK was constitutively associated with Cdk4 in PAEC and that Ang II treatment induced AMPK\u03b2 phosphorylation and subsequent disassociation of this complex. Both Ang II-induced Rb hyperphosphorylation and Cdk4-AMPK disassociation were blocked by the AMPK inhibitor compound C. Together these findings illuminate a novel proapoptotic signaling pathway in endothelial cells, whereby Ang II triggers E2F1-mediated transcriptional upregulation of Bim via activation of AMPK\u03b21\/2 and Cdk4. <\/jats:p>","DOI":"10.1152\/ajplung.00087.2012","type":"journal-article","created":{"date-parts":[[2012,6,2]],"date-time":"2012-06-02T00:44:39Z","timestamp":1338597879000},"page":"L228-L238","source":"Crossref","is-referenced-by-count":19,"title":["Angiotensin II regulates activation of Bim via Rb\/E2F1 during apoptosis: involvement of interaction between AMPK\u03b21\/2 and Cdk4"],"prefix":"10.1152","volume":"303","author":[{"given":"Yong-Chul","family":"Kim","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Uniformed Services University of the Health Sciences, Bethesda, Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Regina M.","family":"Day","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Uniformed 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