Jorge H. Capdevila

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Jorge H. Capdevila
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Born (1940-10-06) October 6, 1940 (age 83)
Santiago, Chile
NationalityAmerican
Alma mater
  • University of Chile
  • University of Georgia
Occupation
  • American Biochemist
  • Professor

Jorge H. Capdevila (October 6, 1940) is an American Biochemist and Professor Emeritus of Medicine at Vanderbilt University Medical School, Nashville TN[1]. He was named Fellow of the American Heart Association in 2002 and received the 2004 American Heart Association prestigious Novartis Award[2] for his contributions to our understanding of the molecular basis of hypertension. Dr. Capdevila’s pioneering identification of roles for the Cytochrome P450 (P450) enzymes in the metabolism of arachidonic acid (AA) and of the physiological and pathophysiological importance of these enzymes and products were recognized in an special section honoring him at the 14th International Winter Eicosanoid Conference, Baltimore MD, March 11-14, 2012[3]. In 2017 Dr. Capdevila received an Outstanding Achievement Award from the Eicosanoid Research Foundation for his contributions to the establishment of the AA Monooxygenase as a physiological/pathophysiological important metabolic pathway[4]. Professor Capdevila is listed as a noteworthy medical and biochemical educator in the 2008 62nd volume of Marquis “Who’s Who in America”.

Early life and career

Dr. Capdevila was born in Santiago, Chile. Married Maria Antonieta Maturana, sons Cristian and Andres. He earned a degree in Biochemistry in 1969 from the University of Chile, Santiago, Chile and a Ph.D. from the University of Georgia, Athens, GA in 1975. He did postdoctoral work with Professors Sten Orrenius at the Karolinska Institutet, Stockholm, Sweden, and Russell A. Prough and Ronald W. Estabrook at the University of Texas Health Science Center at Dallas, TX [now University of Texas Southwestern (UTSW) Medical Center]. Dr. Capdevila initiated his independent research career in 1984 as a Research Assistant Professor of Biochemistry at the UTSW Medical Center, Dallas, TX, joined the faculty at the Vanderbilt University Medical School, Nashville TN in 1986 as Associate Professor of Medicine and Biochemistry, was promoted to Professor in 1991, and retired as Emeritus Professor of Medicine in 2015. Dr. Capdevila has authored 206 peer-reviewed publications and was awarded 5 US patents.

Scientific Contributions

The Cytochrome P450 Arachidonic Acid Monooxygenase Metabolic Pathway: Soon after his initial report of a role for the microsomal P450 enzymes in AA oxidation[5], Dr. Capdevila and collaborators begun studies of the biochemical and enzymatic properties of this novel metabolic pathway5 that resulted in the: a) structural characterization of 5,6-, 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acids (EETs)[6] and 19- and 20-hydroxyeicosatetraenoic acids (19- and 20-HETEs)[7] as products of the Epoxygenase and ω/ω-1 Hydroxylase branches of the P450 AA Monooxygenase[8], respectively, b) identification of the presence of pools of EETs in human and rodent organs and the establishment of the AA Epoxygenase as an endogenous metabolic pathway[9], c) documentation of a role for the P450 CYP2 gene subfamily in endogenous EET biosynthesis[10], d) identification of the presence in human and rodent urine of the EET hydration products, the vic-dihydroxyeicosatrienoic acids (DHETs), and of soluble epoxide hydrolase (sEH) as the enzyme responsible for their formation[11], and e) demonstration that in most organ tissues the EETs are present esterified into cellular glycerophospholipids[12].

Characterization of Functional Roles for the Arachidonic Acid Epoxygenase Metabolites: Early studies by Dr. Capdevila and collaborators showed that EETs stimulated the release of brain, pituitary, and pancreatic hormones[5],[9],[10], mediated signaling by epidermal growth factor[13], inhibited renal Na+ and K+ transport[5][14][15], and possessed vasodilator properties[16]. These were the first reports of EET-associated biological activities and as such, they served as an incentive for subsequent functional studies of the AA Epoxygenase and its metabolites in the USA and abroad.

Physiological/Pathophysiological Roles of the Arachidonic Acid Monooxygenase Pathway: Capdevila’s group provided the first unequivocal evidence that members of the P450 murine Cyp4a and Cyp2c gene subfamilies participated in the control of systemic blood pressures[17] by showing that lack of a functional: a) Cyp4a14 gene caused male specific hypertension associated with increases in the renal expression of the Cyp4a12 AA ω-Hydroxylase and the biosynthesis of the vasoconstrictor 20-HETE[18]. The biomedical relevance of these studies was indicated by the identification of associations between variants in the human CYP4A11 gene (coding for a functional homologue of the murine Cyp4a12 20-HETE synthase) and hypertension in Caucasians[19] and with hypertension and the progression of kidney disease in African-Americans[20]; b) Cyp4a10 gene down-regulated the kidney expression of the Cyp2c44 AA Epoxygenase, leading to reductions in renal EET biosynthesis and dietary salt sensitive hypertension[21], and c) Cyp2c44 gene reduced the kidney biosynthesis and the in vivo levels of 11,12-EET and caused dietary salt sensitive hypertension associated with a hyperactive kidney epithelial sodium channel (ENaC) and increases in sodium reabsorption in the distal nephron[5][22]. These molecular genetics studies identified: a) 20-HETE as a renal vasoconstrictor and pro-hypertensive lipid[5],[18],[19], and b) 11,12-EET as a regulator of ENaC gating, and as an endogenous natriuretic and anti-hypertensive mediator[5],[18],[23]. Additionally, they demonstrated that salt sensitive hypertension, a prevalent form of the human disease, could result from a down-regulation or a lack of a functional Cyp2c44 AA Epoxygenase[5],[18] and suggested similar physiological/pathophysiological roles for its human catalytic homologue, CYP2C8[23].

More recently Dr. Capdevila participated in the elucidation of roles for the Cyp2c44 AA Epoxygenase in tumor vascularization[24] and progression in a rodent model of human non-small-cell-lung cancer[25] (NSCLC), as well as in studies showing improved survival in female cases of NSCLC in carriers of two known reduction of function variants of the human CYP2C9 AA Epoxygenase gene[26].

In summary, Dr. Capdevila and collaborators contributed to the identification of the biological significance of the P450 Arachidonic Acid Monooxygenase, its establishment as the third branch of the Eicosanoid Cascade, and to its current status as a physiological/pathophysiological important metabolic pathway[5].

References

  1. ↑ Furlong, Kara. "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. ↑ 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.
  5. ↑ 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. doi:10.1073/pnas.78.9.5362. PMC 348745. PMID 6795631.
  6. ↑ 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.
  7. ↑ 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.
  8. ↑ 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.
  9. ↑ 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.
  10. ↑ 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.
  11. ↑ Zeldin, D.C.; Kobayashi, J.; Falck, J.R.; Winder, B.S.; Hammock, B.D.; Snapper, J.R.; Capdevila, J.H. (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.
  12. ↑ Karara, A.; Dishman, E.; Falck, J.R.; Capdevila, J.H. (1991). "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. ↑ 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.
  14. ↑ 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.
  15. ↑ 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.
  16. ↑ 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.
  17. ↑ Capdevila, J.H.; Wang, W.; Falck, J.R. (2015). "Arachidonic acid monooxygenase: Genetic and biochemical approaches to physiological/pathophysiological relevance". Prostaglandins and Other Lipid Mediators. 120: 40–49. doi:10.1016/j.prostaglandins.2015.05.004. PMC 4575609. PMID 25986599.
  18. ↑ Holla, V.R.; Adas, F.; Ichihara, S.; Price, E.; Olsen, N.; Kovacs, W.J.; Magnuson, M.A.; Keeney, D.S.; Breyer, M.D.; Falck, J.R.; Waterman, M.R.; Capdevila, J.H. (2001). "Alterations in the regulation of androgen-sensitive Cyp4a monooxygenases cause hypertension". Proceedings of the National Academy of Sciences USA. 98 (9): 5211–5216. doi:10.1073/pnas.081627898. PMC 33189. PMID 11320253.
  19. ↑ Gainer, J.V.; Bellamine, A.; Dawson, E.P.; Womble, K.E.; Grant, S.W.; Wang, Y.; Cupples, A.; Guo, C.Y.; Demissie, S.; O'Donnell, C.J.; Brown, N.J.; Waterman, M.R.; Capdevila, J.H. (2005). "Functional variant of CYP4A11 20-hydroxyeicosatetraenoic acid synthase is associated with essential hypertension". Circulation. 111 (1): 63–69. doi:10.1161/01.CIR.0000151309.82473.59. PMID 15611369.
  20. ↑ Gainer, J.V.; Lipkowitz, M.S.; Yu, C.; Waterman, M.R.; Dawson, E.P.; Capdevila, J.H.; Brown, N.J.; 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.
  21. ↑ Nakagawa, K.; Holla, V.R.; Wei, Y.; Wang, W.H.; Gatica, A.; Wei, S.; Mei, S.; Miller, C.M.; Cha, D.R.; Price, E.; Zent, R.; Pozzi, A.; Breyer, M.D.; Guan, Y.; Falck, J.R.; Waterman, M.R.; Capdevila, J.H. (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.
  22. ↑ Capdevila, J.H.; Pidkovka, N.; Mei, S.; Gong, Y.; Sun, P.; Falck, J.R.; Imig, J.D.; Harris, R.C.; Wang, W.H. (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.
  23. ↑ Zeldin, D.C.; DuBois, R.N.; Falck, J.R.; Capdevila, J.H. (1995). "Molecular cloning, expression, and characterization of an endogenous human cytochrome P450 arachidonic acid epoxygenase isoform". Archives of Biochemistry and Biophysics. 322 (1): 76–86. doi:10.1006/abbi.1995.1438. PMID 7574697.
  24. ↑ 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.
  25. ↑ 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): 621–631. doi:10.1158/0008-5472.CAN-13-1928. PMC 3902646. PMID 24302581.
  26. ↑ 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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