Alterations in the regulation of androgen-sensitive Cyp 4a monooxygenases cause hypertension

Holla, Vijaykumar; Adas, Fadi; Imig, John D.; Zhao, Xueying; Price, Edward; Olsen, Nancy J.; Kovacs, William J.; Magnuson, Mark A.; Keeney, Diane S.; Breyer, Matthew D.; Falck, John R.; Waterman, Michael R.; Capdevila, Jorge H.

doi:10.1073/pnas.081627898

Cited by 222 publications

(329 citation statements)

References 39 publications

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“…In this respect, the CYP4A11 polymorphism is remarkable for consistent findings in several population-based samples, as well as supportive data from a quantitative trait locus for blood pressure on rat chromosome 5 syntenic to human chromosome 1p33-p35, in which CYP4A11 is located, 21 and finally, congruent data from CYP4A14 knockout mice, a gene that is closely related to the human CYP4A11 gene. 7 …”

Section: Limitationsmentioning

confidence: 99%

“…[3][4][5][6] Holla et al characterized a CYP4A14 (Ϫ/Ϫ) knockout mouse as a model of gender-specific severe hypertension. 7 Evaluation of human homologues as potential novel genetic determinants in hypertension revealed 2 candidate genes: CYP4A11 and CYP4A22 from the CYP4A gene family. 8,9 Recently, CYP4A11 but not CYP4A22 was identified as the functional active protein that catalyzes the metabolism of arachidonic acid to 20-HETE in humans.…”

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confidence: 99%

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Association of the T8590C Polymorphism of CYP4A11 With Hypertension in the MONICA Augsburg Echocardiographic Substudy

et al. 2005

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Abstract-Genetic variants of the arachidonic acid monooxygenase CYP4A11 result in decreased synthesis of 20-hydroxyeicostatetraenoic acid and experimental hypertension. Moreover, in humans, the T8590C polymorphism of CYP4A11 displayed association with arterial hypertension. The aim of the present study was to further investigate this association in a large population-based sample. Therefore, the participants of the echocardiographic substudy of the third MONICA (MONitoring trends and determinants In CArdiovascular disease) survey (nϭ1397) were studied by standardized anthropometric, echocardiographic, and biochemical measurements as well as genotyping for CYP4A11 . Consistent with the renal effects of the gene, no blood pressure-independent association between the T8590C polymorphism and echocardiographic parameters of left ventricular function and geometry was found. In conclusion, our data strengthen the association between the T8590C polymorphism of CYP4A11 and hypertension and suggest a recessive mode of inheritance. In contrast, we found no blood pressure-independent modulatory effect of CYP4A11 T8590C on cardiac size, structure, and function. Key Words: genetics Ⅲ polymorphism Ⅲ hypertension, arterial Ⅲ echocardiography A variety of gene variants has shown association with arterial hypertension. However, only small or inconsistent effects on blood pressure were observed for most of the frequent polymorphisms of hypertension-related genes. 1 On the other hand, mutations with profound implications for blood pressure regulation were found predominantly in exceptional families. 2 Thus, despite extensive research, genetic testing for risk assessment in hypertension is not yet advisable for routine patient evaluation. A major challenge for this field will be the identification of genetic variants with reproducible and clinically as well as epidemiologically relevant effects on blood pressure regulation that, in addition, offer the potential of therapeutical intervention.The CYP4A arachidonic acid monooxygenase oxidizes endogenous arachidonic acid to 20-hydroxyeicostatetraenoic acid (20-HETE). Depending on its expression at renovascular or tubular sites, the 20-HETE metabolite can act in a prohypertensive or antihypertensive manner. [3][4][5][6] Holla et al characterized a CYP4A14 (Ϫ/Ϫ) knockout mouse as a model of gender-specific severe hypertension. 7 Evaluation of human homologues as potential novel genetic determinants in hypertension revealed 2 candidate genes: CYP4A11 and CYP4A22 from the CYP4A gene family. 8,9 Recently, CYP4A11 but not CYP4A22 was identified as the functional active protein that catalyzes the metabolism of arachidonic acid to 20-HETE in humans. 10 Screening for genetic variants revealed a cytosine for thymidine transition at nucleotide 8590 in exon 11, which results in a nonsynonymous phenylalanine to serine substitution at residue 434 of CYP4A11. The less frequent 8590C genotype, which corresponds to the 434S variant on protein

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Section: Limitationsmentioning

confidence: 99%

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confidence: 99%

Association of the T8590C Polymorphism of CYP4A11 With Hypertension in the MONICA Augsburg Echocardiographic Substudy

et al. 2005

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“…3,4 Animal studies have previously shown that disruption of the murine Cyp450 4a14 gene results in hypertension, possibly via increased expression of Cyp4a12. 5 20-HETE has been shown to play a role in vasoconstriction and renal salt handling in the spontaneously hypertensive rat. 2,6 -8 In humans, 20-HETE has been shown to play a role in regulation of natriuresis in salt-sensitive and salt-resistant hypertension, 9 and we have previously demonstrated a significant association between urinary 20-HETE excretion and both hypertension and endothelial dysfunction.…”

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confidence: 99%

A Single Nucleotide Polymorphism in the CYP4F2 but not CYP4A11 Gene Is Associated With Increased 20-HETE Excretion and Blood Pressure

et al. 2008

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Abstract-Arachidonic acid is a major fatty acid that can be metabolized by the cytochrome P450 enzyme to a number of bioactive eicosanoids. A major metabolite of this oxidation is 20-hydroxyeicosatetraenoic acid, which acts as a potent vasoconstrictor. However, in the kidney, its vasoconstrictor actions can be offset by its natriuretic properties. A guanine-to-adenine polymorphism in the CYP4F2 gene was associated with a reduction in 20-hydroxyeicosatetraenoic acid production in vitro. A thymidine-to-cytosine polymorphism in the CYP4A11 gene reduced catalytic activity by Ͼ50% in vitro and was associated with hypertension. The aim was to determine whether these 2 mutations are associated with urinary 20-hydroxyeicosatetraenoic acid excretion and blood pressure in humans. For the CYP4F2, 51% were homozygous for the G allele, 40% were carriers, and 9% were homozygous for the A allele. For CYP4A11, 72% were homozygous for the T allele, 25% were carriers, and 3% were homozygous for the C allele. The CYP4F2 GA/AA genotype was significantly associated with an increase in both 20-hydroxyeicosatetraenoic acid excretion and systolic blood pressure. The CYP4A11 CC/TC genotype was significantly associated with a reduction in 20-hydroxyeicosatetraenoic acid excretion but was not associated with blood pressure. We have demonstrated for the first time in humans that polymorphisms of the CYP4F2 and CYP4A11 genes have opposite effects on 20-hydroxyeicosatetraenoic acid excretion. The positive association between the CYP4F2 GA/AA genotype and both systolic blood pressure and 20-hydroxyeicosatetraenoic acid excretion strengthens a role for 20-hydroxyeicosatetraenoic acid in the modulation of blood pressure. A rachidonic acid is a major membrane fatty acid that can be metabolized by the cytochrome P450 (CYP450) enzymes to a range of bioactive compounds. These compounds are thought to play a central role in the regulation of blood pressure (BP), vascular tone, and renal function. 1,2 Within the vasculature, the CYP450 enzymes belonging to the 2-gene family (CYP 2B, 2C8, 2C9, 2C10, and 2J2) are responsible for the production of epoxides, whereas the -hydroxylases belonging to the CYP 4A and 4F families are involved in the production of hydroxyeicosatetraenoic acids (HETEs). 3,4 Animal studies have previously shown that disruption of the murine Cyp450 4a14 gene results in hypertension, possibly via increased expression of Cyp4a12. 5 20-HETE has been shown to play a role in vasoconstriction and renal salt handling in the spontaneously hypertensive rat. 2,6 -8 In humans, 20-HETE has been shown to play a role in regulation of natriuresis in salt-sensitive and salt-resistant hypertension, 9 and we have previously demonstrated a significant association between urinary 20-HETE excretion and both hypertension and endothelial dysfunction. 10 Paradoxically, within the kidney, 20-HETE can have either prohypertensive or antihypertensive actions, depending on its site of production. In the renal tubule, 20-HETE inhibits tubular sodium reabsorpti...

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“…16 RNA analysis revealed that Cyp4a10 is the predominant 4a isoform expressed in the kidney cortex of wild-type adult male mice, followed by Cyp4a12 and low levels of Cyp4a14 transcripts. 17 Genetic disruption of the Cyp4a14 gene in mice results in sexually dimorphic spontaneous hypertension, with male mice being hypertensive and female mice being normotensive. 17 Hypertension in Cyp4a14(2/2) (Cyp4a14KO) mice is caused by elevated levels of circulating plasma androgens that induce Cyp4a12 expression in the kidney cortex and biosynthesis of 20-HETE.…”

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Hypertension Is a Major Contributor to 20-Hydroxyeicosatetraenoic Acid–Mediated Kidney Injury in Diabetic Nephropathy

Gangadhariah

Luther

García

et al. 2015

Journal of the American Society of Nephrology

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In the kidney, 20-hydroxyeicosatetraenoic acid (20-HETE) is a primary cytochrome P450 4 (Cyp4)-derived eicosanoid that enhances vasoconstriction of renal vessels and induces hypertension, renal tubular cell hypertrophy, and podocyte apoptosis. Hypertension and podocyte injury contribute to diabetic nephropathy and are strong predictors of disease progression. In this study, we defined the mechanisms whereby 20-HETE affects the progression of diabetic nephropathy. We used Cyp4a14KO male mice that exhibit androgen-sensitive hypertension due to increased Cyp4a12-mediated 20-HETE production. We show that, upon induction of diabetes type 1 via streptozotocin injection, Cyp4a14KO male mice developed worse renal disease than streptozotocin-treated wild-type mice, characterized by increased albuminuria, mesangial expansion, glomerular matrix deposition, and thickness of the glomerular basement membranes. Castration blunted androgen-mediated Cyp4a12 synthesis and 20-HETE production, normalized BP, and ameliorated renal damage in diabetic Cyp4a14KO mice. Notably, treatment with a 20-HETE antagonist or agents that normalized BP without affecting Cyp4a12 expression and 20-HETE biosynthesis also ameliorated diabetesmediated renal damage and albuminuria in Cyp4a14KO male mice. Taken together, these results suggest that hypertension is the major contributor to 20-HETE-driven diabetes-mediated kidney injury.

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Alterations in the regulation of androgen-sensitive Cyp 4a monooxygenases cause hypertension

Cited by 222 publications

References 39 publications

Association of the T8590C Polymorphism of CYP4A11 With Hypertension in the MONICA Augsburg Echocardiographic Substudy

Association of the T8590C Polymorphism of CYP4A11 With Hypertension in the MONICA Augsburg Echocardiographic Substudy

A Single Nucleotide Polymorphism in the CYP4F2 but not CYP4A11 Gene Is Associated With Increased 20-HETE Excretion and Blood Pressure

Hypertension Is a Major Contributor to 20-Hydroxyeicosatetraenoic Acid–Mediated Kidney Injury in Diabetic Nephropathy

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