Mice lacking hypertension candidate gene ATP2B1 in vascular smooth muscle cells show significant blood pressure elevation.
We reported previously that ATP2B1 was one of the genes for hypertension receptivity in a large-scale Japanese population, which has been replicated recently in Europeans and Koreans. ATP2B1 encodes the plasma membrane calcium ATPase isoform 1, which plays a critical role in intracellular calcium homeostasis. In addition, it is suggested that ATP2B1 plays a major role in vascular smooth muscle contraction. Because the ATP2B1 knockout (KO) mouse is embryo-lethal, we generated mice with vascular smooth muscle cell-specific KO of ATP2B1 using the Cre-loxP system to clarify the relationship between ATP2B1 and hypertension. The KO mice expressed significantly lower levels of ATP2B1 mRNA and protein in the aorta compared with control mice. KO mice showed significantly higher systolic blood pressure as measured by tail-cuff method and radiotelemetric method. Similar to ATP2B1, the expression of the Na(+)-Ca(2+) exchanger isoform 1 mRNA was decreased in vascular smooth muscle cells of KO mice. However, ATP2B4 expression was increased in KO mice. The cultured vascular smooth muscle cells of KO mice showed increased intracellular calcium concentration not only in basal condition but also in phenylephrine-stimulated condition. Furthermore, phenylephrine-induced vasoconstriction was significantly increased in vascular rings of the femoral artery of KO mice. These results suggest that ATP2B1 plays important roles in the regulation of blood pressure through alteration of calcium handling and vasoconstriction in vascular smooth muscle cells.
Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School ofMedicine, Yokohama, Japan.
Yusuke
Y
Kobayashi
Nobuhito
N
Hirawa
Yasuharu
Y
Tabara
Hidenori
H
Muraoka
Megumi
M
Fujita
Nobuko
N
Miyazaki
Akira
A
Fujiwara
Yasuhiro
Y
Ichikawa
Yuichiro
Y
Yamamoto
Naoaki
N
Ichihara
Sanae
S
Saka
Hiromichi
H
Wakui
Shin-ichiro
S
Yoshida
Keisuke
K
Yatsu
Yoshiyuki
Y
Toya
Gen
G
Yasuda
Katsuhiko
K
Kohara
Yoshikuni
Y
Kita
Kohtaro
K
Takei
Yoshio
Y
Goshima
Yoshihiro
Y
Ishikawa
Hirotsugu
H
Ueshima
Tetsuro
T
Miki
Satoshi
S
Umemura
D000818:Animals; D001794:Blood Pressure / Q000502:physiology*; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005263:Femoral Artery / Q000187:drug effects / Q000502:physiology; D017353:Gene Deletion; D006706:Homeostasis / Q000502:physiology; D006973:Hypertension / Q000235:genetics* / Q000503:physiopathology*; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D010656:Phenylephrine / Q000494:pharmacology; D053499:Plasma Membrane Calcium-Transporting ATPases / Q000172:deficiency / Q000235:genetics*; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology
D010656:Phenylephrine; D053499:Plasma Membrane Calcium-Transporting ATPases; C506954:Atp2b1 protein, mouse; D002118:Calcium