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. 2008 Apr;19(4):714-21.
doi: 10.1681/ASN.2007060713. Epub 2008 Jan 30.

Association of a functional cytochrome P450 4F2 haplotype with urinary 20-HETE and hypertension

Hong Liu  1 , Yanyan Zhao, Dong Nie, Jingpu Shi, Lingyu Fu, Yan Li, Dahai Yu, Jingyu Lu
Affiliations

Association of a functional cytochrome P450 4F2 haplotype with urinary 20-HETE and hypertension

Hong Liu et al. J Am Soc Nephrol. 2008 Apr.

Abstract

Cytochrome P450 4F2 (CYP4F2) catalyzes the omega-hydroxylation of arachidonic acid to 20-hydroxyeicosatetraenoic acid (20-HETE), a natriuretic and vasoactive eicosanoid that participates in the development of hypertension. The relationship among CYP4F2 genetic variants in the regulatory region, formation of renal 20-HETE, and hypertension is unknown. Here are reported seven genetic variants around the CYP4F2 intronic regulatory region. Four of these variants made up two common haplotypes, Hap I (c.-91T/c.-48G/c.-13T/c.+34T) and Hap II (c.-91C/c.-48C/c.-13C/c.+34G). Hap I included a major functional variant, c.-91T-->C, which was identified by reporter assay and electrophoretic mobility shift assay. Transfected into HEK293 cells, the Hap I construct showed a trend toward higher basal transcriptional activity and exhibited significantly greater LPS-stimulated activity than Hap II; these findings were the result of different NF-kappaB binding affinity between the two constructs. In vivo, a case-control study demonstrated that homozygosity for Hap I doubled the risk for hypertension in a Chinese population, even after adjustment for risk factors including age, gender, and body mass index. This association was confirmed in a family-based association study. In addition, Hap I was associated with elevated urinary 20-HETE. These results indicate that a functional variant of the CYP4F2 regulatory region, which increases the binding affinity of NF-kappaB, increases the risk for hypertension, likely by modulating the production of 20-HETE.

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Figures

Figure 1.
Figure 1.
Map of the CYP4F2 gene around the regulatory region. Exons are indicated by bold letters, and the coding amino acid sequence is shown below the DNA sequence. The DNA sequencing region was from c.−209 to c.+419. Nucleotides were numbered according to the Genebank reference sequence AF467894, where the A of the ATG translation initiation codon is +1. The discovered genetic variants are denoted by arrows. Boxed sequences represent the basal cis-acting elements and putative binding sites of NF-κB and Myb.
Figure 2.
Figure 2.
Transcriptional activities of reporter constructs in the transfected HEK293 cells. (A) The series of deletion constructs with the c.−91T→C, c.−48G→C, and c.−13T→C variants. (B) Transcriptional activities of Hap I and Hap II in pCAT564, pCAT219, and pCAT67. (C) Transcriptional activities of pCAT219 constructs with different combination of the c.−91T→C and c.−48G→C variants. All experiments were performed three times independently. *P < 0.05.
Figure 3.
Figure 3.
EMSA with HEK293 nuclear extract. (A) Sense strands of putative NF-κB binding site. (B) Radiolabeled oligonucleotides NF-κB consensus (lanes 1 to 5), c.−91T (lanes 6 to 9), and c.−91C (lanes 10 to 12) were bound with nuclear extract. Competition assay was performed by adding 100- and 500-fold excess of unlabeled oligonucleotides. Radiolabeled c.−91T and c.−91C were bound with nuclear extract (lanes 13 and 15) and in the presence of p50 antibody (lanes 14 and 16). *Radiolabeled oligonucleotides. con., consensus oligonucleotide; anti-p50, p50 antibody; ns, nonspecific.
Figure 4.
Figure 4.
The basal and LPS-stimulated transcriptional activities of Hap I and Hap II in various reporter constructs. The final concentration of LPS is 1 μg/ml. *P < 0.05. All experiments were performed three times independently.
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References

    1. Lasker JM, Chen WB, Wolf I, Bloswick BP, Wilson PD, Powell PK: Formation of 20-hydroxyeicosatetraenoic acid, a vasoactive and natriuretic eicosanoid, in human kidney: Role of Cyp4F2 and Cyp4A11. J Biol Chem 275: 4118–4126, 2000 - PubMed
    1. Kikuta Y, Kusunose E, Kusunose M: Characterization of human liver leukotriene B4-hydroxylase P450 (CYP4F2). J Biochem 127: 1047–1052, 2000 - PubMed
    1. Sontag TJ, Parker RS: Cytochrome P450 omega-hydroxylase pathway of tocopherol catabolism: Novel mechanism of regulation of vitamin E status. J Biol Chem 277: 25290–25296, 2002 - PubMed
    1. McGiff JC, Quilley J: 20-HETE and the kidney: Resolution of old problems and new beginnings. Am J Physiol 277: R607–R623, 1999 - PubMed
    1. Roman RJ: P-450 metabolites of arachidonic acid in the control of cardiovascular function. Physiol Rev 82: 131–185, 2002 - PubMed

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