TY - JOUR
T1 - Steroid biosynthesis and renal excretion in human essential hypertension
T2 - Association with blood pressure and endogenous ouabain
AU - Tripodi, Grazia
AU - Citterio, Lorena
AU - Kouznetsova, Tatiana
AU - Lanzani, Chiara
AU - Florio, Monica
AU - Modica, Rossana
AU - Messaggio, Elisabetta
AU - Hamlyn, John M.
AU - Zagato, Laura
AU - Bianchi, Giuseppe
AU - Staessen, Jan A.
AU - Manunta, Paolo
PY - 2009/4
Y1 - 2009/4
N2 - Background: Endogenous ouabain (EO) has been linked with long-term changes in sodium balance and cardiovascular structure and function. The biosynthesis of EO involves, cholesterol side-chain cleavage (CYP11A1), 3-β-hydroxysteroid dehydrogenase (HSD3B) with sequential metabolism of pregnenolone and progesterone. Furthermore, the renal excretion of cardiac glycosides is mediated by the organic anion transporter (SLCO4C1) at the basolateral membrane and the P-glycoprotein (PGP) (encoded by MDR1) at the apical membrane of the nephron. Methods: Average 24-h ambulatory blood pressures were recorded in 729 untreated essential hypertensives. Aldosterone (Aldo), EO, urinary Na+, and K+ excretions were determined. Single-nucleotide polymorphism (SNP) and haplotype-based association study was performed with a total of 26 informative SNPs. Results: Plasma EO was significantly directly related to both day (r = 0.131, P <0.01) and nighttime diastolic blood pressure (DBP) (r = 0.143, P <0.01), and remained significantly related after correction for confounders (sex, body mass index, age). Genotype analysis for EO levels and daytime DBP gave significant results for CYP11A1 rs11638442 and MDR1 rs1045642 (T/C Ile1145) in which the minor allele tracked with higher EO levels (T/T 210.3 (147-272) vs. C/C 270.7 (193-366) pmol/l, P <0.001). Association was found between HSD3B1 polymorphisms and/or haplotypes with blood pressure (systolic blood pressure (SBP) 140.3 (11.7) vs. 143.8 (11.2) mm Hg, P <0.01) and plasma Aldo (P <0.05). Haplotype-based analyses support the data of SNP analysis. Conclusions: Among patients with essential hypertension, cholesterol side-chain cleavage and MDR1 loci are related to circulating EO and DBP, most likely by influencing EO synthesis and transmembrane transport, respectively. In contrast, variants in HSD3B1 are related with SBP probably via Aldo.
AB - Background: Endogenous ouabain (EO) has been linked with long-term changes in sodium balance and cardiovascular structure and function. The biosynthesis of EO involves, cholesterol side-chain cleavage (CYP11A1), 3-β-hydroxysteroid dehydrogenase (HSD3B) with sequential metabolism of pregnenolone and progesterone. Furthermore, the renal excretion of cardiac glycosides is mediated by the organic anion transporter (SLCO4C1) at the basolateral membrane and the P-glycoprotein (PGP) (encoded by MDR1) at the apical membrane of the nephron. Methods: Average 24-h ambulatory blood pressures were recorded in 729 untreated essential hypertensives. Aldosterone (Aldo), EO, urinary Na+, and K+ excretions were determined. Single-nucleotide polymorphism (SNP) and haplotype-based association study was performed with a total of 26 informative SNPs. Results: Plasma EO was significantly directly related to both day (r = 0.131, P <0.01) and nighttime diastolic blood pressure (DBP) (r = 0.143, P <0.01), and remained significantly related after correction for confounders (sex, body mass index, age). Genotype analysis for EO levels and daytime DBP gave significant results for CYP11A1 rs11638442 and MDR1 rs1045642 (T/C Ile1145) in which the minor allele tracked with higher EO levels (T/T 210.3 (147-272) vs. C/C 270.7 (193-366) pmol/l, P <0.001). Association was found between HSD3B1 polymorphisms and/or haplotypes with blood pressure (systolic blood pressure (SBP) 140.3 (11.7) vs. 143.8 (11.2) mm Hg, P <0.01) and plasma Aldo (P <0.05). Haplotype-based analyses support the data of SNP analysis. Conclusions: Among patients with essential hypertension, cholesterol side-chain cleavage and MDR1 loci are related to circulating EO and DBP, most likely by influencing EO synthesis and transmembrane transport, respectively. In contrast, variants in HSD3B1 are related with SBP probably via Aldo.
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U2 - 10.1038/ajh.2009.3
DO - 10.1038/ajh.2009.3
M3 - Article
C2 - 19197249
AN - SCOPUS:62849089258
VL - 22
SP - 357
EP - 363
JO - American Journal of Hypertension
JF - American Journal of Hypertension
SN - 0895-7061
IS - 4
ER -