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Tatiana Kuznetsova University of Leuven, Belgium

The InGenious HyperCare European Network: A3. JRP on Genetics and Genomics of Sodium Homeostasis in the Pathogenesis of Hypertension and Left Ventricular Hypertrophy ENDOGENOUS OUABAIN (EO): from genotypes to cardiovascular structure and function. Tatiana Kuznetsova

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Tatiana Kuznetsova University of Leuven, Belgium

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  1. The InGenious HyperCare European Network: A3. JRP on Genetics and Genomics of Sodium Homeostasis in the Pathogenesis of Hypertension and Left Ventricular Hypertrophy ENDOGENOUS OUABAIN (EO): from genotypes to cardiovascular structure and function Tatiana Kuznetsova University of Leuven, Belgium

  2. JRP A3 Outline • Endogenous ouabain: possible mechanism. • Preliminary results • Perspectives

  3. JRP A3 Endogenous ouabain • In genetic forms of HT, salt sensitivity may result from various mutations affecting cytoskeleton proteins (such as adducin), ion transporters, or endocrine/paracrine factors (such as endogenous ouabain and aldosterone). • In experimental studies, EO had direct effects on BP and was associated with TOD (Ferrandi M. et al, Front Biosci 2005).

  4. . Ouabain Structural formula of ouabain • Ouabain: • cardiotonic steroid (analogue of digitalis) • cardenolides

  5. Ouabain Modulator of the Na+- K+ pump EO through direct Na-K pump interaction Heart, vessels Kidney a1 Na-K pump Src-EGFr-dependent Tyr phosphorylation Classical a2 Na-K pump inhibition Overall tubular Na+ reabsorption Na/Ca exchange [Ca2+]i Volume expansion Hypertrophy Hypertension Ferrari P et al., Am J Physiology 2006;290:R529-R535

  6. Ouabain 160 150 140 130 Infusion in rats (15 mg/kg/day) Plus oral treatment with PST 2238 (10 mg/kg ) or amlodipine (5 mg/kg) Systolic BP *** mmHg ### ### Left ventricle weight 1.85 1.75 LVW / tibia lenght # * 1.65 1.55 1.45 control OS OS + PST 2238 OS + amlodipine *p<0.05, **p<0.01 vs control; #p<0.05, ###p<0.001 vs ouabain

  7. Ouabain Objective • We investigated the distribution of plasma ouabain in the general population in relation to LV structure and function, arterial phenotypes, and BP. • We explored the association of LV and arterial phenotypes with genes involved in the biosynthesis of EO.

  8. Flemengho Epidemiological methods Randomly recruited families (Flemish Study on Environment, Genes and Health Outcomes); Standardised and validated questionnaires; A single observer did the echocardiographical examinations by means of Vivid 7 ultrasound scanner (GE Vingmed, Horten, Norway); We measured plasma EO in 434 subjects by radioimmunoassay, using a specific antiserum.

  9. LV LV phenotypes Teichholz Volume EF(%) IVST - PWT RWT = LVDD

  10. LVF Transmitral blood flow vs pulsed Tissue Doppler Imaging A E Aa Ea

  11. Flemengho Clinical characteristics *P0.05

  12. LV Echocardiographic characteristics † P0.001

  13. Ouabain Association with LV wall thickness LV wall thickness RWT Posterior wall Septum Ouabain quartiles (pmol/L) Adjusted for gender, age, bmi, sbp, and antihypertensive treatment

  14. Ouabain Association with LV mass and carotid IMT LVM IMT Ouabain quartiles (pmol/L) Adjusted for gender, age, bmi, sbp, and antihypertensive treatment

  15. Ouabain Association with BP SBP DBP All; n=434 Untreated; n=324 Ouabain quartiles (pmol/l) Adjusted for gender, age, age2, bmi, and antihypertensive treatment

  16. Ouabain Familial aggregation of EO level • Intrafamilial correlation coefficient for EO was 0.15; P = 0.023 • Candidate genes were selected from a putative steroid biosynthetic pathway (Murrell J.R. et al, Circulation 2005)

  17. Ouabain Steroidogenic genes • Three genes of the biosynthetic pathway of EO are over-expressed in MHS genetic hypertensive rats: • Cholesterol side chain cleavage cytochrome P450: CYP11A1; • 3β hydroxy-steroid deydrogenase: HSD3B1; • Lanosterol synthase: LSS. • In hypertensive patients, plasma EO was associated with variation in HSD3B1 and LSS.

  18. Ouabain LV phenotypes by the HSD3B1 and CYP11A1 genes 11 12 22 P HSD3B1 (rs2236780 and rs3765945) GG haplotype N --- 70 438 TDI Ea/Aa --- 1.02 1.18 0.0026 CYP11A1 (rs11638442) N 182 233 93 LVM (g) 174.5 176.7 160.9 0.0037

  19. Ouabain Perspectives • Our preliminary results show that BP and LV wall thickness are associated with plasma EO. • Genetic variation in the EO pathways, via BP and/or LV structure/function might contribute to risk stratification in clinical practice, pending a full screen of the candidate genes. • Phenotype-genotype associations involving functionally relevant SNPs will then be replicated in ongoing echocardiographic studies within the consortium (Kraków, Gdansk, Novosibirsk, Padova, and Valencia).

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