In the ‘Millennium Genome Project’, we identified ATP2B1 as a gene responsible for hypertension through single-nucleotide polymorphism analysis. The ATP2B1 gene encodes the plasma membrane calcium ATPase isoform 1, which contributes to the maintenance of intracellular calcium homeostasis by removing calcium ions.
Since ATP2B1 knockout mice are reported to be embryo-lethal, we generated systemic heterozygous ATP2B1 null (ATP2B1+/−) mice, and evaluated the implication of ATP2B1 in blood pressure.
ATP2B1+/− mice revealed significantly higher SBP as measured by a radiotelemetric method. Phenylephrine-induced vasoconstriction was significantly increased in vascular rings from ATP2B1+/− mice, and the difference in this contraction disappeared in the presence of a nitric oxide synthase (NOS) inhibitor. Vasorelaxation to acetylcholine was significantly attenuated in vascular rings from ATP2B1+/− mice. In addition, cultured endothelial cells of ATP2B1+/− mice showed that the phosphorylation (Ser-1177) level of endothelial NOS protein was significantly lower, and nitric oxide production in endothelial cells and aorta was lower compared with those in control mice. In contrast, neural NOS expression in vascular smooth muscle cells from ATP2B1+/− mice and control mice were not significantly different.
These results suggest that decreased ATP2B1 gene expression is associated with impaired endothelial NOS activity and nitric oxide production, and the ATP2B1 gene plays a crucial role in the regulation of blood pressure.
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aDepartment of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine
bDepartment of Nephrology and Hypertension, Yokohama City University Medical Center
cMolecular Pharmacology and Neurobiology, Yokohama City University Graduate School of Medicine, Yokohama
dCenter for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto
eDepartment of Geriatric Medicine, Ehime University Graduate School of Medicine, Toon
fDepartment of Health Science, Shiga University of Medical Science, Otsu
gCardiovascular Research Institute, Yokohama City University Graduate School of Medicine, Yokohama, Japan
Correspondence to Nobuhito Hirawa, MD, PhD, Department of Nephrology and Hypertension, Yokohama City University Medical Center, 45-7, Urafune-cho, Minami-ku, Yokohama 232-0024, Japan.Tel: +81 45 261 5656; fax: +81 45 253 9955; e-mail: email@example.com
Abbreviations: ATP2B1+/− mice, systemic heterozygous ATP2B1 null mice; eNOS, endothelial nitric oxide synthase; L-NAME, Nω-nitro-L-arginine methyl ester; NOx, nitrate/nitrite; NCX, sodium/calcium exchanger; nNOS, neural nitric oxide synthase; NOS, nitric oxide synthase; PMCA, plasma membrane calcium ATPase isoform; qRT-PCR, quantitative reverse transcription-PCR; SERCA, sarco-endoplasmic reticulum Ca2+-ATPase; SNP, single-nucleotide polymorphism; VSMC, vascular smooth muscle cell
Received 18 August, 2013
Revised 17 March, 2014
Accepted 17 March, 2014
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