• Source: Jorge H. Capdevila

Jorge H. Capdevila (born October 6, 1940) is an American biochemist and professor emeritus of medicine at Vanderbilt University Medical School. 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" 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). Capdevila received an "Outstanding Achievement Award" from the Eicosanoid Research Foundation at their 15th International Bioactive Lipid Conference (2017).




Personal life


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




Career


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. 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)]. 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. Capdevila has authored 206 peer-reviewed publications and was awarded five US patents.




Scientific contributions






= 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, Capdevila initiated studies of the biochemical and enzymatic properties of this novel metabolic pathway that led to the initial: a) structural identification of the 5,6-, 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acids (EETs) and 19- and 20-hydroxyeicosatetraenoic acids (19- and 20-HETE) as products of the Epoxygenase Omega Hydroxylase branches of the P450 AA
Monooxygenase respectively; and b) characterization of the EETs as products of the in vivo metabolism of AA by rodent and human organs and of the AA epoxygenase as an endogenous metabolic pathway. Subsequently, Capdevila's laboratory identified: a) roles for P450s of the CYP2 gene subfamily in EETs endogenous biosynthesis; b) the presence of novel pools of endogenous glycerolipids containing esterified EET moities; 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. The development of inhibitors of sEH activity to control organ EET levels and functional properties is an area of current interest.




= 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, mediated signaling by epidermal growth factor, inhibited renal Na+ and K+ transport in isolated collecting ducts, and possessed vasodilator properties. 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.




= 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, members of the P450 murine Cyp4a and Cyp2c gene subfamilies participated in the control of systemic blood pressures 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. 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) and hypertension in White Americans, hypertension, the progression of kidney disease in African-Americans, and risk of hypertension in German and Japanese cohorts; 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; 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. Abnormalities in the regulation of urinary EET pools in normotensive, dietary salt-sensitive, individuals have been reported. Collectively, these studies identified: a) 20-HETE as a renal vasoconstrictor and pro-hypertensive lipid; and b) 11,12-EET as an endogenous natriuretic and anti-hypertensive mediator. Additionally, they demonstrated that salt-sensitive hypertension could result from either a down regulation or lack of a functional Cyp2c44 epoxygenase. These achievements, highlighted in independent reviews, 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 and progression in rodent models of human non-small-cell-lung cancer (NSCLC); 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.
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.




References

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