{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T19:09:28Z","timestamp":1790104168881,"version":"4.0.1"},"reference-count":29,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2025,3,13]],"date-time":"2025-03-13T00:00:00Z","timestamp":1741824000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Canzonetti Foundation Fund","award":["300129"],"award-info":[{"award-number":["300129"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Inhibition of HIF-prolyl hydroxylases (PHD1, PHD2, and PHD3) causes the stabilization of hypoxia-inducible factor-1\u03b1 and -2\u03b1 (HIF-1\u03b1 and HIF-2\u03b1) to regulate various cell signaling pathways. Hypoxia-inducible factor (HIF) is crucial in regulating signal responses mediated by hypoxia. HIF regulates the transcription of many genes involved in the response to hypoxia and ischemic insult. Our current work investigates the protective effects of PHD1 knockout in mice against myocardial infarction. Study Design: Myocardial infarction (MI) was induced by left anterior descending coronary artery (LAD) ligation (8\u201312-week-old mice) in both wild-type (WT) and PHD1 knockout (PHD1\u2212\/\u2212) mice. WT sham (S) and PHD1\u2212\/\u2212S group mice underwent surgery without LAD ligation. Thirty days post-surgery, cardiac functions were measured by echocardiogram. Mice in all the groups were euthanized at various time points for tissue collection post-MI 8 h (gel shift and microarray analysis), 4 days (Western blot analysis), 7 days (blood vessel density), or 30 days (histological analysis). For microarray analysis, WTMI and PHD1\u2212\/\u2212MI group mices\u2019 heart tissue was used for RNA isolation, then hybridization to a GeneChip\u2122 Mouse Gene 1.0 ST Array as per the manufacturer\u2019s instructions. Bioinformatic analysis was performed using the transcriptome analysis console (TAC) to generate a list of differentially regulated genes, followed by ingenuity pathway analysis. Results: The study findings revealed a significant increase in vessel density (capillary and arteriolar density) in the PHD1\u2212\/\u2212MI mice compared to those with WTMI. The echocardiographic examination demonstrated that the PHD1\u2212\/\u2212MI mice group had an increased ejection fraction and fractional shortening than the WT mice 30 days post-MI. HIF-1\u03b1 DNA binding activity was higher in PHD1\u2212\/\u2212MI mice than in WTMI. The Western blot analysis showed a significant increase in the expression of HSPA12B in the PHD1\u2212\/\u2212MI compared to WTMI mice. Bioinformatic analysis using TAC software, Version 4.0.2.15 (1.5 fold, p &lt; 0.05) showed 174 differentially regulated genes. Conclusions: In conclusion, our study showed PHD1 knockout activates several important molecules and signaling pathways, resulting in increased angiogenesis and cardioprotection against myocardial infarction.<\/jats:p>","DOI":"10.3390\/cells14060423","type":"journal-article","created":{"date-parts":[[2025,3,13]],"date-time":"2025-03-13T04:18:32Z","timestamp":1741839512000},"page":"423","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Stabilization of Transcription Factor, HIF-1\u03b1 by Prolylhydroxylase 1 Knockout Reduces Cardiac Injury After Myocardial Infarction in Mice"],"prefix":"10.3390","volume":"14","author":[{"given":"Mahesh","family":"Thirunavukkarasu","sequence":"first","affiliation":[{"name":"Molecular Cardiology and Angiogenesis Laboratory, Department of Surgery, University of Connecticut School of Medicine, UConn Health, Farmington, CT 06030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seetur R.","family":"Pradeep","sequence":"additional","affiliation":[{"name":"Molecular Cardiology and Angiogenesis Laboratory, Department of Surgery, University of Connecticut School of Medicine, UConn Health, Farmington, CT 06030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Babatunde","family":"Oriowo","sequence":"additional","affiliation":[{"name":"Molecular Cardiology and Angiogenesis Laboratory, Department of Surgery, University of Connecticut School of Medicine, UConn Health, Farmington, CT 06030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4023-8369","authenticated-orcid":false,"given":"Sue Ting","family":"Lim","sequence":"additional","affiliation":[{"name":"Molecular Cardiology and Angiogenesis Laboratory, Department of Surgery, University of Connecticut School of Medicine, UConn Health, Farmington, CT 06030, USA"},{"name":"Stanley J. Dudrick, Department of Surgery, Trinity Health of New England\u2014Saint Mary\u2019s Hospital, Waterbury, CT 06706, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monica","family":"Maloney","sequence":"additional","affiliation":[{"name":"Molecular Cardiology and Angiogenesis Laboratory, Department of Surgery, University of Connecticut School of Medicine, UConn Health, Farmington, CT 06030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shayan","family":"Ahmed","sequence":"additional","affiliation":[{"name":"Molecular Cardiology and Angiogenesis Laboratory, Department of Surgery, University of Connecticut School of Medicine, UConn Health, Farmington, CT 06030, USA"},{"name":"Stanley J. Dudrick, Department of Surgery, Trinity Health of New England\u2014Saint Mary\u2019s Hospital, Waterbury, CT 06706, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole","family":"Taylor","sequence":"additional","affiliation":[{"name":"Molecular Cardiology and Angiogenesis Laboratory, Department of Surgery, University of Connecticut School of Medicine, UConn Health, Farmington, CT 06030, USA"},{"name":"Stanley J. Dudrick, Department of Surgery, Trinity Health of New England\u2014Saint Mary\u2019s Hospital, Waterbury, CT 06706, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David M.","family":"Russell","sequence":"additional","affiliation":[{"name":"Molecular Cardiology and Angiogenesis Laboratory, Department of Surgery, University of Connecticut School of Medicine, UConn Health, Farmington, CT 06030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pavayee","family":"Socrates","sequence":"additional","affiliation":[{"name":"Molecular Cardiology and Angiogenesis Laboratory, Department of Surgery, University of Connecticut School of Medicine, UConn Health, Farmington, CT 06030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ethan","family":"Batko","sequence":"additional","affiliation":[{"name":"Molecular Cardiology and Angiogenesis Laboratory, Department of Surgery, University of Connecticut School of Medicine, UConn Health, Farmington, CT 06030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matan","family":"Berkovsky","sequence":"additional","affiliation":[{"name":"Molecular Cardiology and Angiogenesis Laboratory, Department of Surgery, University of Connecticut School of Medicine, UConn Health, Farmington, CT 06030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John Alexander","family":"Palesty","sequence":"additional","affiliation":[{"name":"Stanley J. Dudrick, Department of Surgery, Trinity Health of New England\u2014Saint Mary\u2019s Hospital, Waterbury, CT 06706, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1585-1783","authenticated-orcid":false,"given":"Nilanjana","family":"Maulik","sequence":"additional","affiliation":[{"name":"Molecular Cardiology and Angiogenesis Laboratory, Department of Surgery, University of Connecticut School of Medicine, UConn Health, Farmington, CT 06030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,3,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1016\/j.suc.2022.01.007","article-title":"Epidemiology of Coronary Artery Disease","volume":"102","author":"Duggan","year":"2022","journal-title":"Surg. Clin. N. Am."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"181","DOI":"10.4330\/wjc.v16.i4.181","article-title":"Hypoxia-inducible factor-1\u03b1 in myocardial infarction","volume":"16","author":"Kolomeichuk","year":"2024","journal-title":"World J. Cardiol."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Chen, C., Wang, J., Liu, C., Hu, J., and Liu, L. (2023). Pioneering therapies for post-infarction angiogenesis: Insight into molecular mechanisms and preclinical studies. Biomed. Pharmacother., 166.","DOI":"10.1016\/j.biopha.2023.115306"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"798","DOI":"10.1016\/j.hlc.2023.05.018","article-title":"Therapeutic Angiogenesis Using Growth Factors After Myocardial Infarction: From Recombinant Proteins to Gene Therapies and Beyond","volume":"32","author":"Deshmukh","year":"2023","journal-title":"Heart Lung Circ."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1182\/blood-2013-09-512749","article-title":"Oxidative stress in angiogenesis and vascular disease","volume":"123","author":"Kim","year":"2014","journal-title":"Blood"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Luo, Z., Tian, M., Yang, G., Tan, Q., Chen, Y., Li, G., Zhang, Q., Li, Y., Wan, P., and Wu, J. (2022). Hypoxia signaling in human health and diseases: Implications and prospects for therapeutics. Signal Transduct. Target. Ther., 7.","DOI":"10.1038\/s41392-022-01080-1"},{"key":"ref_7","first-page":"51","article-title":"Hypoxia-Inducible Factor (HIF)-1 regulatory pathway and its potential for therapeutic intervention in malignancy and ischemia","volume":"80","author":"Ziello","year":"2007","journal-title":"Yale J. Biol. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2631","DOI":"10.1089\/ars.2013.5186","article-title":"Molecular mechanisms of action and therapeutic uses of pharmacological inhibitors of HIF-prolyl 4-hydroxylases for treatment of ischemic diseases","volume":"20","author":"Selvaraju","year":"2014","journal-title":"Antioxid. Redox Signal"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/j.mvr.2014.10.009","article-title":"Deletion of prolyl hydroxylase domain proteins (PHD1, PHD3) stabilizes hypoxia inducible factor-1 alpha, promotes neovascularization, and improves perfusion in a murine model of hind-limb ischemia","volume":"97","author":"Rishi","year":"2015","journal-title":"Microvasc. Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1305","DOI":"10.2174\/13816128113199990549","article-title":"Targeted gene deletion of prolyl hydroxylase domain protein 3 triggers angiogenesis and preserves cardiac function by stabilizing hypoxia inducible factor 1 alpha following myocardial infarction","volume":"20","author":"Oriowo","year":"2014","journal-title":"Curr. Pharm. Des."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1097\/XCS.0000000000000241","article-title":"Protective Effect of Cardiomyocyte-Specific Prolyl-4-Hydroxylase 2 Inhibition on Ischemic Injury in a Mouse MI Model","volume":"235","author":"Pradeep","year":"2022","journal-title":"J. Am. Coll. Surg."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Andersen, S., Donnem, T., Stenvold, H., Al-Saad, S., Al-Shibli, K., Busund, L.T., and Bremnes, R.M. (2011). Overexpression of the HIF hydroxylases PHD1, PHD2, PHD3 and FIH are individually and collectively unfavorable prognosticators for NSCLC survival. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0023847"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/S0092-8674(01)00507-4","article-title":"elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation","volume":"107","author":"Epstein","year":"2001","journal-title":"Cell"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"468","DOI":"10.1126\/science.1059796","article-title":"Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation","volume":"292","author":"Jaakkola","year":"2001","journal-title":"Science"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"38458","DOI":"10.1074\/jbc.M406026200","article-title":"Differential function of the prolyl hydroxylases PHD1, PHD2, and PHD3 in the regulation of hypoxia-inducible factor","volume":"279","author":"Appelhoff","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"4082","DOI":"10.1093\/emboj\/cdg392","article-title":"HIF prolyl-hydroxylase 2 is the key oxygen sensor setting low steady-state levels of HIF-1alpha in normoxia","volume":"22","author":"Berra","year":"2003","journal-title":"Embo J."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"42719","DOI":"10.1074\/jbc.M406713200","article-title":"Genetic analysis of the role of the asparaginyl hydroxylase factor inhibiting hypoxia-inducible factor (FIH) in regulating hypoxia-inducible factor (HIF) transcriptional target genes [corrected]","volume":"279","author":"Stolze","year":"2004","journal-title":"J. Biol. Chem"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1097\/FJC.0b013e3181e2bfef","article-title":"Chronic inhibition of hypoxia-inducible factor prolyl 4-hydroxylase improves ventricular performance, remodeling, and vascularity after myocardial infarction in the rat","volume":"56","author":"Bao","year":"2010","journal-title":"J. Cardiovasc. Pharmacol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1143","DOI":"10.1053\/j.gastro.2009.09.057","article-title":"Loss or silencing of the PHD1 prolyl hydroxylase protects livers of mice against ischemia\/reperfusion injury","volume":"138","author":"Schneider","year":"2010","journal-title":"Gastroenterology"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1038\/ng.2007.62","article-title":"Deficiency or inhibition of oxygen sensor Phd1 induces hypoxia tolerance by reprogramming basal metabolism","volume":"40","author":"Schneider","year":"2008","journal-title":"Nat. Genet."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1789","DOI":"10.1089\/ars.2010.3769","article-title":"Disruption of hypoxia-inducible transcription factor-prolyl hydroxylase domain-1 (PHD-1\u2212\/\u2212) attenuates ex vivo myocardial ischemia\/reperfusion injury through hypoxia-inducible factor-1\u03b1 transcription factor and its target genes in mice","volume":"15","author":"Adluri","year":"2011","journal-title":"Antioxid. Redox Signal"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"8336","DOI":"10.1128\/MCB.00425-06","article-title":"Placental but not heart defects are associated with elevated hypoxia-inducible factor alpha levels in mice lacking prolyl hydroxylase domain protein 2","volume":"26","author":"Takeda","year":"2006","journal-title":"Mol. Cell. Biol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1007\/978-1-60761-175-2_7","article-title":"PANTHER pathway: An ontology-based pathway database coupled with data analysis tools","volume":"563","author":"Mi","year":"2009","journal-title":"Methods Mol. Biol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2628","DOI":"10.1093\/bioinformatics\/btz931","article-title":"ShinyGO: A graphical gene-set enrichment tool for animals and plants","volume":"36","author":"Ge","year":"2020","journal-title":"Bioinformatics"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Selvaraju, V., Thirunavukkarasu, M., Joshi, M., Oriowo, B., Shaikh, I.A., Rishi, M.T., Tapias, L., Coca-Soliz, V., Saad, I., and Campbell, J. (2020). Deletion of newly described pro-survival molecule Pellino-1 increases oxidative stress, downregulates cIAP2\/NF-\u03baB cell survival pathway, reduces angiogenic response, and thereby aggravates tissue function in mouse ischemic models. Basic Res. Cardiol., 115.","DOI":"10.1007\/s00395-020-0804-4"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Thirunavukkarasu, M., Selvaraju, V., Joshi, M., Coca-Soliz, V., Tapias, L., Saad, I., Fournier, C., Husain, A., Campbell, J., and Yee, S.P. (2018). Disruption of VEGF Mediated Flk-1 Signaling Leads to a Gradual Loss of Vessel Health and Cardiac Function During Myocardial Infarction: Potential Therapy with Pellino-1. J. Am. Heart. Assoc., 7.","DOI":"10.1161\/JAHA.117.007601"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1007\/s12265-017-9734-4","article-title":"Regulation of A-Kinase-Anchoring Protein 12 by Heat Shock Protein A12B to Prevent Ventricular Dysfunction Following Acute Myocardial Infarction in Diabetic Rats","volume":"10","author":"Selvaraju","year":"2017","journal-title":"J. Cardiovasc. Transl. Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1007\/s40262-017-0551-3","article-title":"Phase I Clinical Study of ZYAN1, A Novel Prolyl-Hydroxylase (PHD) Inhibitor to Evaluate the Safety, Tolerability, and Pharmacokinetics Following Oral Administration in Healthy Volunteers","volume":"57","author":"Kansagra","year":"2018","journal-title":"Clin. Pharmacokinet."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1007\/s40265-019-01077-1","article-title":"Roxadustat: First global approval","volume":"79","author":"Dhillon","year":"2019","journal-title":"Drugs"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/14\/6\/423\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T16:52:43Z","timestamp":1760028763000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/14\/6\/423"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,13]]},"references-count":29,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2025,3]]}},"alternative-id":["cells14060423"],"URL":"https:\/\/doi.org\/10.3390\/cells14060423","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,3,13]]}}}