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Jorge H. Capdevila

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Jorge H. Capdevila
Born (1940-10-06) October 6, 1940 (age 84)
Santiago, Chile
Alma materUniversity of Chile, University of Georgia
OccupationBiochemist
SpouseMaria Antonieta Maturana
Children2

Jorge H. Capdevila (born October 6, 1940) is an American biochemist and professor emeritus of medicine at Vanderbilt University Medical School.[1] He was named fellow of the American Heart Association in 2002 and received the 2004 American Heart Association's "Novartis Excellence Award for Hypertension Research"[2] for his contributions to our understanding of the molecular basis of hypertension. Capdevila's identification of roles for Cytochrome P450 (P450) in the metabolism of arachidonic acid (AA) and of the physiological and pathophysiological importance of these enzymes and their products were recognized in a special section honoring him at the 14th International Winter Eicosanoid Conference (2012).[3] Capdevila received an "Outstanding Achievement Award" from the Eicosanoid Research Foundation at their 15th International Bioactive Lipid Conference (2017).[4][5]

Personal life

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Capdevila was born in Santiago, Chile. He and his wife, Maria Antonieta Maturana, have two sons.[citation needed]

Career

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Capdevila obtained a degree in biochemistry in 1969 from the University of Chile, Santiago, Chile, and in 1975 a Ph.D. from the University of Georgia. [1] He did postdoctoral work with Sten Orrenius at the Karolinska Institutet, as well as with Russell A. Prough and Ronald W. Estabrook at the University of Texas Health Science Center at Dallas (now University of Texas Southwestern Medical Center (UTSW)].[1] He initiated his independent research career in 1984 as a Research Assistant Professor of Biochemistry at the UTSW Medical Center). In 1986 he joined the faculty at the Vanderbilt University Medical School as associate professor of medicine and biochemistry, was promoted to professor in 1991, and retired as emeritus professor of medicine in 2015.[1] Capdevila has authored 206 peer-reviewed publications and was awarded five US patents.[1]

Scientific contributions

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The Cytochrome P450 Arachidonic Acid Monooxygenase Metabolic Pathway

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After his 1981 report of roles for the microsomal P450 enzymes in AA oxidation,[6] Capdevila initiated studies of the biochemical and enzymatic properties of this novel metabolic pathway[5] that led to the initial: a) structural identification of the 5,6-, 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acids (EETs)[7] and 19- and 20-hydroxyeicosatetraenoic acids (19- and 20-HETE)[8] as products of the Epoxygenase Omega Hydroxylase branches of the P450 AA Monooxygenase[5][9][10] respectively; and b) characterization of the EETs as products of the in vivo metabolism of AA by rodent and human organs[11] and of the AA epoxygenase as an endogenous metabolic pathway.[9][10][11] Subsequently, Capdevila's laboratory identified: a) roles for P450s of the CYP2 gene subfamily in EETs endogenous biosynthesis;[11] b) the presence of novel pools of endogenous glycerolipids containing esterified EET moities;[12] and c) soluble epoxide hydrolase (sEH)(Epoxide hydrolase 2) as the enzyme that catalyzes EET hydration to vic-dihydroxyeicosatrienoic acids (DHETs) prior to their urinary excretion.[9][13] The development of inhibitors of sEH activity to control organ EET levels and functional properties is an area of current interest.[14]

Characterization of Functional Roles for the Arachidonic Acid Epoxygenase Metabolites

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Early studies by Capdevila and collaborators showed that EETs stimulated the release of brain, pituitary, and pancreatic hormones,[5][9][10] mediated signaling by epidermal growth factor,[15] inhibited renal Na+ and K+ transport in isolated collecting ducts,[5][9][16][17] and possessed vasodilator properties.[18] These were the first reports of EET-associated in vitro biological activities, and as such, they served as an incentive to subsequent extended studies of the functional roles and physiological/pathophysiological significance of the AA epoxygenase and its metabolites.[19][20][21][22][23]

Physiological and Pathophysiological Roles of the Arachidonic Acid Monooxygenase Pathway

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Capdevila's research group provided unequivocal genetic and biochemical evidence that, as suggested earlier,[24] members of the P450 murine Cyp4a and Cyp2c gene subfamilies participated in the control of systemic blood pressures[25] by showing that targeted disruption of the: a) Cyp4a14 gene caused a type of hypertension that was male-specific and associated with increases in plasma androgens, the renal expression of the Cyp4a12 AA omega hydroxylase, and the biosynthesis of pro-hypertensive 20-HETE.[19][26] The potential clinical relevance of these studies was highlighted by reports of associations between a functional variant of the human CYP4A11 20-HETE synthase (the T8590C polymorphism)[27] and hypertension in White Americans,[27][28] hypertension, the progression of kidney disease in African-Americans,[29] and risk of hypertension in German and Japanese cohorts;[30] b) Cyp4a10 gene downregulated the expression of the kidney Cyp2c44 epoxygenase, leading to reductions in renal EET biosynthesis and the development of dietary salt sensitive hypertension;[31] and c) Cyp2c44 gene caused dietary salt-sensitive hypertension linked to reductions in renal EET biosynthesis and excretion, as well as increases in sodium retention in the distal nephron.[32] Abnormalities in the regulation of urinary EET pools in normotensive, dietary salt-sensitive, individuals have been reported.[33] Collectively, these studies identified: a) 20-HETE as a renal vasoconstrictor and pro-hypertensive lipid;[19][22][23][25] and b) 11,12-EET as an endogenous natriuretic and anti-hypertensive mediator.[5][17][25][32] Additionally, they demonstrated that salt-sensitive hypertension could result from either a down regulation or lack of a functional Cyp2c44 epoxygenase.[5][25][31] These achievements, highlighted in independent reviews,[19][20][21][22][23] contributed as an stimulant to ongoing efforts to further define the physiological and pathophysiological relevance of the AA Monooxygenase enzymes and its metabolites, as well as potentially novel targets for drug development.

More recently, Capdevila participated in: a) the identification of roles for the Cyp2c44 epoxygenases and the EETs in tumor vascularization[34] and progression in rodent models of human non-small-cell-lung cancer (NSCLC);[35] and b) in clinical studies showing improved survival in female cases of NSCLC that were carriers of two known reduction of function variants of the human CYP2C9 epoxygenase gene.[36]

In summary, Capdevila and collaborators contributed to the initial discovery and characterization of roles for the CYP450 monooxygenases in the metabolism and bio-activation of endogenous arachidonic acid, the identification of its role in the in vivo regulation of cell, organ, and body physiology, and to its present status as a physiological/pathophysiological important metabolic pathway.[5]

References

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  1. ^ a b c d e Furlong, Kara (8 May 2015). "Vanderbilt University honors 28 as emeriti faculty". Vanderbilt University.
  2. ^ Harder, David R. (April 21, 2005). "Preface". Hypertension. 45 (4): 633–634. doi:10.1161/01.HYP.0000160454.86957.90 – via CrossRef.
  3. ^ Brown, NJ; Falck, J.R. (2013). "P450 metabolites of arachidonic acid-from biochemistry to therapy". Prostaglandins and Other Lipid Mediators. 104–105 (1): 1. doi:10.1016/j.prostaglandins.2013.06.003. PMID 23809194.
  4. ^ "Outstanding Achievement Award – Bioactive Lipids in Cancer, Inflammation and Related Diseases".
  5. ^ a b c d e f g h Capevila, J.H.; Falck, J.R. (2018). "The arachidonic acid monooxygenase: From biochemical curiosity to physiological/pathophysiological significance". Journal of Lipid Research. 59 (11): 2047–2062. doi:10.1194/jlr.R087882. PMC 6210905. PMID 30154230.
  6. ^ Capdevila, J.; Chacos, N.; Werringloer, J.; Prough, R.A.; Estabrook, R.W. (1981). "Liver microsomal cytochrome P-450 and the oxidative metabolism of arachidonic acid". Proceedings of the National Academy of Sciences USA. 78 (9): 5362–5366. Bibcode:1981PNAS...78.5362C. doi:10.1073/pnas.78.9.5362. PMC 348745. PMID 6795631.
  7. ^ Chacos, N.; Falck, J.R.; Wixtrom, C.; Capdevila, J. (1982). "Novel epoxides formed during the liver cytochrome P-450 oxidation of arachidonic acid". Biochemistry and Biophysical Research Communications. 104 (3): 916–922. doi:10.1016/0006-291x(82)91336-5. PMID 6803794.
  8. ^ Manna, S.; Falck, J.R.; Chacos, N.; Capdevila, J. (1983). "Synthesis of arachidonic acid metabolites produced by purified kidney cortex microsomal cytochrome P-450". Tetrahedron Letters. 24 (1): 33–36. doi:10.1016/S0040-4039(00)81319-2.
  9. ^ a b c d e Capdevila, J.H.; Falck, J.R.; Harris, R.C. (2000). "Cytochrome P450 and arachidonic acid bioactivation: Molecular and functional properties of the arachidonate monooxygenase". Journal of Lipid Research. 41 (2): 271–292. doi:10.1016/S0022-2275(20)32049-6. PMID 10963794.
  10. ^ a b c Capdevila, J.H.; Falck, J.R. (2000). "Biochemical and molecular characteristics of the cytochrome P450 arachidonic acid monooxygenase". Prostaglandins and Other Lipid Mediators. 62 (3): 271–292. doi:10.1016/s0090-6980(00)00085-x. PMID 10963794.
  11. ^ a b c Karara, A.; Dishman, E.; Blair, I.; Falck, J.R.; Capdevila, J.H. (1989). "Cytochrome P-450 controlled stereoselectivity of the hepatic arachidonic acid epoxygenase". Journal of Biological Chemistry. 264 (33): 19822–19827. doi:10.1016/S0021-9258(19)47185-8. PMID 2584196.
  12. ^ Karara, A; Dishman, E; Falck, JR; Capdevila, JH (1991). "Endogenous epoxyeicosatrienoyl-phospholipids. A novel class of cellular glycerolipids containing epoxidized arachidonate moieties". Journal of Biological Chemistry. 266 (12): 7561–7569. doi:10.1016/S0021-9258(20)89484-8. PMID 1902222.
  13. ^ Zeldin, DC; Kobayashi, J; Falck, JR; Winder, BS; Hammock, BD; Snapper, JR; Capdevila, JH (1993). "Regio and enantiofacial selectivity of epoxyeicosatrienoic acid hydration by cytosolic epoxide hydratase". Journal of Biological Chemistry. 268 (9): 6402–6407. doi:10.1016/S0021-9258(18)53266-X. PMID 8454612.
  14. ^ Morisseau, C.; Hammock, B. D. (2013). "Impact of soluble epoxide hydrolase and epoxyeicosanoids on human health". Annual Review of Pharmacology and Toxicology. 53: 37–58. doi:10.1146/annurev-pharmtox-011112-140244. PMC 3578707. PMID 23020295.
  15. ^ Chen, J.K.; Capdevila, J.H.; Harris, R.C. (2002). "Heparin-binding EGF-like growth factor mediates the biological effects of P450 arachidonate metabolites in epithelial cells". Proceedings of the National Academy of Sciences USA. 99 (9): 6029–6034. doi:10.1073/pnas.092671899. PMC 122896. PMID 11983897.
  16. ^ Capdevila, J.H. (2007). "Regulation of ion transport and blood pressure by cytochrome P450 monooxygenases". Current Opinion in Nephrology and Hypertension. 16 (5): 465–470. doi:10.1097/MNH.0b013e32827ab48c. PMID 17693763. S2CID 38554014.
  17. ^ a b Capdevila, J.H.; Wang, W.H. (2013). "Role of P450 epoxygenase in regulating renal membrane transport and hypertension". Current Opinion in Nephrology and Hypertension. 22 (2): 163–169. doi:10.1097/MNH.0b013e32835d911e. PMC 3893099. PMID 23302865.
  18. ^ Procto, K.G.; Falck, J.R.; Capdevila, J. (1987). "Intestinal vasodilation by epoxyeicosatrienoic acids: Arachidonic acid metabolites produced by a cytochrome P-450 monoxygenase". Circulation Research. 60 (1): 50–59. doi:10.1161/01.res.60.1.50. PMID 3105909.
  19. ^ a b c d McGiff, JC; Quilley, J. (2001). "20-Hydroxyeicosatetraenoic acid and epoxyeicosatrienoic acids and blood pressure". Current Opinion in Nephrology and Hypertension. 10 (2): 231–237. doi:10.1097/00041552-200103000-00012. PMID 11224699. S2CID 44774278. Retrieved 18 January 2024.
  20. ^ a b Roman, RJ (2002). "P450 Metabolites of arachidonic acid in the control of cardiovascular function". Physiological Reviews. 82 (1): 131–185. doi:10.1152/physrev.00021.2001. PMID 11773611. Retrieved 18 January 2024.
  21. ^ a b Spector, AA; Fang, X; Snyder, GD; Weintraub, NL (2004). "Epoxyeicosatrienoic acids (EETs): metabolism and biochemical function". Progress in Lipid Research. 43 (1): 55–90. doi:10.1016/s0163-7827(03)00049-3. PMID 14636671. Retrieved 24 January 2024.
  22. ^ a b c Fan, Fan; Muroya, Y; Roman, RJ (2015). "Cytochrome P450 eicosanoids in hypertension and renal disease". Current Opinion in Nephrology and Hypertension. 24 (1): 37–46. doi:10.1097/MNH.0000000000000088. PMC 4260681. PMID 25427230.
  23. ^ a b c Imig, JD (2019). "Epoxyeicosanoids in hypertension". Physiological Research. 68 (5): 695–704. doi:10.33549/physiolres.934291. PMC 6941753. PMID 31475560.
  24. ^ Sacerdoti, D; Escalante, B; Abraham, NG; McGiff, JC; Schwartzman, ML (1989). "Treatment with tin prevents the development of hypertension in spontaneously hypertensives rats". Science. 243 (4889): 388–390. Bibcode:1989Sci...243..388S. doi:10.1126/science.2492116. PMID 2492116. Retrieved 25 January 2024.
  25. ^ a b c d Capdevila, JH; Wang, W; Falck, JR (2015). "Arachidonic acid monooxygenase: genetic and biochemical approaches to physiological/pathophysiological relevance". Prostaglandins and Other Other Lipid Mediators. 120: 40–49. doi:10.1016/j.prostaglandins.2015.05.004. PMC 4575609. PMID 25986599.
  26. ^ Holla, VR; Adas, F; Ichihara, S; Price, E; Olsen, N; Kovacs, WJ; Magnuson, MA; Keeney, DS; Breyer, MD; Falck, JR; Waterman, MR; Capdevila, JH (2001). "Alterations in the regulation of androgen sensitive Cyp4a monooxygenases cause hypertension". Proceedings of the National Academy of Sciences USA. 98 (9): 5211–5216. Bibcode:2001PNAS...98.5211H. doi:10.1073/pnas.081627898. PMC 33189. PMID 11320253.
  27. ^ a b Gainer, JV; Bellamine, A; Dawson, EP; Womble, KE; Grant, SW; Wang, Y; Cupples, A; Guo, CY; Demissie, S; O'Donnell, CJ; Brown, NJ; Waterman, MR; Capdevila, JH (2005). "A functional variant of CYP4A11 20-HETE synthase is associated with essential". Circulation. 111 (1): 63–69. doi:10.1161/01.CIR.0000151309.82473.59. PMID 15611369. S2CID 2157088. Retrieved 25 January 2024.
  28. ^ Williams, JS; Hopkins, PN; Jeunemaitre, C; Brown, NJ (2011). "CYP4A11 T8590C polymorphism, salt sensitive hypertension, and renal blood flow". Journal of Hypertension. 29 (10): 1913–1918. doi:10.1097/HJH.0b013e32834aa786. PMC 3309034. PMID 21873888.
  29. ^ Gainer, JV; Lipkowitz, MS; Yu, C; Waterman, MR; Dawson, EP; Capdevila, JH; Brown, NJ; AASK Study Group (2008). "Association of a CYP4A11 variant and blood pressure in black men". Journal of the American Society of Nephrology. 19 (8): 1606–1612. doi:10.1681/ASN.2008010063. PMC 2488260. PMID 18385420.
  30. ^ Zhang, C; Wang, L; Liao, Q; Zhang, L; Xu, L; Chen, C; Ye, H; Xu, X; Ye, M; Duan, S (2013). "Genetic associations with hypertension: Meta-Analysis of six candidate genetic variants". Genetic Testing and Molecular Biomarkers. 17 (10): 736–742. doi:10.1089/gtmb.2013.0080. PMC 3780324. PMID 23859711.
  31. ^ a b Nakagawa, K; Holla, VR; Wei, Y; Wang, WH; Gatica, A; Wei, S; Mei, S; Miller, CM; Cha, DR; Price, E; Zent, R; Pozzi, A; Breyer, MD; Guan, Y; Falck, JR; Waterman, MR; Capdevila, JH (2006). "Salt sensitive hypertension is associated with a dysfunctional Cyp4a10 gene and kidney epithelial sodium channel". Journal of Clinical Investigation. 116 (6): 1696–2302. doi:10.1172/JCI27546. PMC 1459070. PMID 16691295.
  32. ^ a b Capdevila, JH; Pidkovka, N; Mei, S; Gong, Y; Sun, P; Falck, JR; Imig, JD; Harris, RC; Wang, WH (2014). "The Cyp2c44 epoxygenase regulates renal distal sodium excretion and the blood pressure responses to increased dietary salt intake". Journal of Biological Chemistry. 289 (7): 4377–4386. doi:10.1074/jbc.M113.508416. PMC 3924300. PMID 24368771.
  33. ^ Elijovich, F; Milne, GL; Brown, NJ; Schwartzman, ML; Laffer, CL (2018). "Two pools of epoxyeicosatrienoic acids in humans. alterations in salt-sensitive normotensive subjects". Hypertension. 71 (2): 346–355. doi:10.1161/HYPERTENSIONAHA.117.10392. PMC 5764817. PMID 29279315.
  34. ^ Pozzi, A.; Popescu, V.; Yang, S.; Mei, S.; Shi, M.; Puolitaival, S.; Caprioli, R.M.; Capdevila, J.H. (2010). "The anti-tumorigenic properties of the peroxisomal proliferator-activated receptor alpha are arachidonic acid epoxygenase-mediated". Journal of Biological Chemistry. 285 (17): 12840–12850. doi:10.1074/jbc.M109.081554. PMC 2857132. PMID 20178979.
  35. ^ Skyrpnky, N.; Che, X.; Hu, W.; Su, Y.; Mont, S.; Yang, S.; Gangadhariah, M.; Wei, S.; Falck, J.R.; Jat, J.L.; Zent, R.; Capdevila, J.H.; Pozzi, A. (2014). "PPARα activation can help prevent and treat non-small cell lung cancer". Cancer Research. 74 (2): 62 1–631. doi:10.1158/0008-5472.CAN-13-1928. PMC 3902646. PMID 24302581.
  36. ^ Sausville, L.N.; Gangadhariah, M.; Chiusa, M.; Mei, S.; Wei, S.; Zent, R.; Luther, J.M.; Shuey, M.M.; Capdevila, J.H.; Falck, J.R.; Guengerich, F.P.; Williams, S.M.; Pozzi, A. (2018). "The cytochrome P450 slow metabolizers CPY2C9*2 and CYP2C9*3 directly regulate tumorigenesis via reduced epoxyeicosatrienoic acid production". Cancer Research. 78 (17): 4865–4877. doi:10.1158/0008-5472.CAN-17-3977. PMC 6125168. PMID 30012669.
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