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BACKGROUND: Recent genome-wide association studies (GWASs) have identified 30 genetic loci that regulate blood pressure, increasing our understanding of the cause of hypertension. However, it has been difficult to define the causative genes at these loci due to a lack of functional analyses. METHOD: In this study, we aimed to validate the candidate gene ATP2B1 in 12q21, variants near which have the strongest association with blood pressure in Asians and Europeans. ATP2B1 functions as a calcium pump to fine-tune calcium concentrations - necessary for repolarization following muscular contractions. We silenced Atp2b1 using an siRNA complex, injected into mouse tail veins. RESULTS: In treated mice, blood pressure rose and the mesenteric arteries increased in wall : lumen ratio. Moreover, the arteries showed enhanced myogenic responses to pressure, and contractile responses to phenylephrine increased compared with the control, suggesting that blood pressure is regulated by ATP2B1 through the contraction and dilation of the vessel, likely by controlling calcium concentrations in the resting state. CONCLUSION: These results support that ATP2B1 is the causative gene in the blood pressure-associated 12q21 locus and demonstrate that ATP2B1 expression in the vessel influences blood pressure.

Original publication

DOI

10.1097/HJH.0b013e32836189e9

Type

Journal article

Journal

J Hypertens

Publication Date

08/2013

Volume

31

Pages

1575 - 1583

Keywords

Animals, Blood Pressure, Calcium, Gene Silencing, Genome-Wide Association Study, Mice, Mice, Inbred BALB C, NIH 3T3 Cells, Phenylephrine, Plasma Membrane Calcium-Transporting ATPases, RNA, Small Interfering, Real-Time Polymerase Chain Reaction, Risk Factors, Time Factors, Vasoconstriction