Increased NBCn1 expression, Na+/HCO- 3 co-transport and intracellular pH in human vascular smooth muscle cells with a risk allele for hypertension
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Increased NBCn1 expression, Na+/HCO- 3 co-transport and intracellular pH in human vascular smooth muscle cells with a risk allele for hypertension. / Ng, Fu Liang; Boedtkjer, Ebbe; Witkowska, Kate; Ren, Meixia; Zhang, Ruoxin; Tucker, Arthur; Aalkjær, Christian; Caulfield, Mark J.; Ye, Shu.
In: Human Molecular Genetics, Vol. 26, No. 5, ddx015, 2017, p. 989-1002.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Increased NBCn1 expression, Na+/HCO- 3 co-transport and intracellular pH in human vascular smooth muscle cells with a risk allele for hypertension
AU - Ng, Fu Liang
AU - Boedtkjer, Ebbe
AU - Witkowska, Kate
AU - Ren, Meixia
AU - Zhang, Ruoxin
AU - Tucker, Arthur
AU - Aalkjær, Christian
AU - Caulfield, Mark J.
AU - Ye, Shu
PY - 2017
Y1 - 2017
N2 - Genome-wide association studies have revealed an association between variation at the SLC4A7 locus and blood pressure. SLC4A7 encodes the electroneutral Na+/HCO- 3 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.
AB - Genome-wide association studies have revealed an association between variation at the SLC4A7 locus and blood pressure. SLC4A7 encodes the electroneutral Na+/HCO- 3 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.
U2 - 10.1093/hmg/ddx015
DO - 10.1093/hmg/ddx015
M3 - Journal article
C2 - 28087731
AN - SCOPUS:85019072808
VL - 26
SP - 989
EP - 1002
JO - Human Molecular Genetics
JF - Human Molecular Genetics
SN - 0964-6906
IS - 5
M1 - ddx015
ER -
ID: 196713514