{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T02:46:17Z","timestamp":1789785977179,"version":"4.0.1"},"reference-count":52,"publisher":"American Physiological Society","issue":"3","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Journal of Applied Physiology"],"published-print":{"date-parts":[[2004,3]]},"abstract":"<jats:p> The cardiovascular and respiratory systems play key roles in O<jats:sub>2<\/jats:sub> homeostasis. Physiological responses to hypoxia involve changes in gene expression that are mediated by the transcriptional activator hypoxia-inducible factor (HIF)-1. Analysis of mice heterozygous for a knockout allele at the locus encoding the O<jats:sub>2<\/jats:sub>-regulated HIF-1\u03b1 or HIF-2\u03b1 subunit has revealed that these proteins are required for multiple physiological responses to chronic hypoxia, including erythrocytosis and pulmonary vascular remodeling. In mice with partial HIF-2\u03b1 deficiency, hypoxia-induced expression of endothelin-1 and norepinephrine is dramatically impaired, and the mice fail to develop pulmonary hypertension after 4 wk of exposure to 10% O<jats:sub>2<\/jats:sub>. In mice with partial HIF-1\u03b1 deficiency, the ability of the carotid body to sense and\/or respond to acute or chronic hypoxia is lost. In wild-type mice, brief episodes of intermittent hypoxia are sufficient to induce production of erythropoietin (EPO), which protects the heart against apoptosis after ischemia-reperfusion, whereas in mice with partial HIF-1\u03b1 deficiency, intermittent hypoxia does not induce EPO production or cardiac protection. Parenteral administration of EPO to rodents is sufficient to induce dramatic protection against ischemia-reperfusion injury in the heart. Thus HIF-1 mediates critical physiological responses to hypoxia, and the elucidation of these homeostatic mechanisms may lead to novel therapies for the most common causes of mortality in the US population. <\/jats:p>","DOI":"10.1152\/japplphysiol.00770.2003","type":"journal-article","created":{"date-parts":[[2004,2,6]],"date-time":"2004-02-06T01:28:50Z","timestamp":1076030930000},"page":"1173-1177","source":"Crossref","is-referenced-by-count":230,"title":["O<sub>2<\/sub>-regulated gene expression: transcriptional control of cardiorespiratory physiology by HIF-1"],"prefix":"10.1152","volume":"96","author":[{"given":"Gregg L.","family":"Semenza","sequence":"first","affiliation":[{"name":"McKusick-Nathans Institute of Genetic Medicine and Program in Vascular Cell Engineering, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"24","reference":[{"key":"REF1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.1995.268.3.H1165"},{"key":"REF2","doi-asserted-by":"publisher","DOI":"10.1002\/1531-8249(200009)48:3<285::AID-ANA2>3.0.CO;2-8"},{"key":"REF3","doi-asserted-by":"publisher","DOI":"10.1152\/jappl.1980.49.6.964"},{"key":"REF4","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.97.19.10526"},{"key":"REF5","doi-asserted-by":"publisher","DOI":"10.1172\/JCI15496"},{"key":"REF6","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000078635.89229.8A"},{"key":"REF7","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2003.045112"},{"key":"REF8","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0630444100"},{"key":"REF9","doi-asserted-by":"publisher","DOI":"10.1038\/28867"},{"key":"REF10","doi-asserted-by":"publisher","DOI":"10.1152\/jappl.1995.79.6.2122"},{"key":"REF11","doi-asserted-by":"publisher","DOI":"10.1038\/nm1102-1329b"},{"key":"REF12","doi-asserted-by":"crossref","unstructured":"DiCarlo VS, Chen SJ, Meng QC, Durand J, Yano M, Chen YF, and Oparil S. 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