title: Increased NBCn1 expression, Na+/HCO3- co-transport and intracellular pH in human vascular smooth muscle cells with a risk allele for hypertension.
abstract: Genome-wide association studies have revealed an association between variation at the SLC4A7 locus and blood pressure. SLC4A7 encodes the electroneutral Na+/HCO3- co-transporter NBCn1 which regulates intracellular pH (pHi). We conducted a functional study of variants at this locus in primary cultures of vascular smooth muscle and endothelial cells. In both cell types, we found genotype-dependent differences for rs13082711 in DNA-nuclear protein interactions, where the risk allele is associated with increased SLC4A7 expression level, NBCn1 availability and function as reflected in elevated steady-state pHi and accelerated recovery from intracellular acidosis. However, in the presence of Na+/H+ exchange activity, the SLC4A7 genotypic effect on net base uptake and steady-state pHi persisted only in vascular smooth muscle cells but not endothelial cells. We found no discernable effect of the missense polymorphism resulting in the amino acid substitution Glu326Lys. The finding of a genotypic influence on SLC4A7 expression and pHi regulation in vascular smooth muscle cells provides an insight into the molecular mechanism underlying the association of variation at the SLC4A7 locus with blood pressure.
authors.affiliation: Department of Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors.forename: Fu Liang
authors.initials: FL
authors.lastname: Ng
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus, Denmark.
authors.forename: Ebbe
authors.initials: E
authors.lastname: Boedtkjer
authors.affiliation: Department of Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors.forename: Kate
authors.initials: K
authors.lastname: Witkowska
authors.affiliation: Department of Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors.forename: Meixia
authors.initials: M
authors.lastname: Ren
authors.affiliation: Department of Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors.forename: Ruoxin
authors.initials: R
authors.lastname: Zhang
authors.affiliation: Department of Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors.forename: Arthur
authors.initials: A
authors.lastname: Tucker
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus, Denmark.|Department of Biomedicine, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Christian
authors.initials: C
authors.lastname: Aalkjær
authors.affiliation: Department of Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Caulfield
authors.affiliation: Department of Cardiovascular Sciences, University of Leicester, Leicester, UK.|NIHR Biomedical Research Centre in Cardiovascular Disease, Leicester, UK.|Shantou University Medical College, Shantou, China.
authors.forename: Shu
authors.initials: S
authors.lastname: Ye
mesh_terms: D000483:Alleles; D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D001794:Blood Pressure / Q000235:genetics; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D042783:Endothelial Cells / Q000378:metabolism; D005786:Gene Expression Regulation; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D006863:Hydrogen-Ion Concentration; D006973:Hypertension / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000473:pathology; D009154:Mutation; D051381:Rats; D012964:Sodium / Q000378:metabolism; D027982:Sodium-Bicarbonate Symporters / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; C422022:SLC4A7 protein, human; C498902:Slc4a7 protein, rat; D027982:Sodium-Bicarbonate Symporters; D012964:Sodium