TY - JOUR
T1 - Impaired Ca2+ Homeostasis and Decreased Orai1 Expression Modulates Arterial Hyporeactivity to Vasoconstrictors During Endotoxemia
AU - Nonato, Arthur Oliveira
AU - Olivon, Vania C.
AU - Dela Justina, Vanessa
AU - Zanotto, Camila Z.
AU - Webb, R Clinton
AU - Tostes, Rita C.
AU - Lima, Victor V.
AU - Giachini, Fernanda R.
N1 - Funding Information:
This work was supported in part by Fundação de Amparo à Pesquisa do Estado de Mato Grosso (FAPEMAT) [grant number 151371/2014 (to F.R.G.], Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) [grant number 23038009165/2013-48 (to V.V.L.], Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) [grant number 2010/52214-6 (to R.C.T)], Conselho Nacional de Desenvolvimento Científico e Tecnológico [(CNPq) 471675/2013-0 and 305823/2015-9 (to F.R.G), 445777/2014-1 (V.V.L.)], and National Institutes of Health (NIH) [HL71138 and DK83685 (R.C.W)]. We would also like to thank all the technical staff, who have worked in our laboratories and contributed to the studies described here.
Publisher Copyright:
© 2016, Springer Science+Business Media New York.
PY - 2016/6/1
Y1 - 2016/6/1
N2 - We hypothesized that SIRS/endotoxemia-associated hyporesponsiveness to vasoconstrictors is mediated by smaller increases in intracellular Ca2+ levels due to reduced signaling via the STIM/Orai. Male Wistar rats were injected either with saline or bacterial LPS (i.p.; 10 mg/kg), and experiments were performed 24 h later. LPS-injected rats exhibited decreased systolic blood pressure, increased heart rate, neutrophils’ migration into the peritoneal cavity, and elevated alanine aminotransferase levels. Additionally, second-order mesenteric arteries from endotoxemic rats displayed hyporeactivity to contractile agents such as phenylephrine and potassium chloride; decreased contractile responses to Ca2+; reduced contraction during Ca2+ loading; and smaller intracellular Ca2+ stores. Decreased Orai1, but not STIM1, expression was found in resistance mesenteric arteries from LPS-treated rats. Additionally, cultured vascular smooth muscle cell (VSMC) treated with LPS resulted in increased TLR-4 expression, but Myd-88 and STIM-1 expression were not changed. Our data suggest that in endotoxemia, Ca2+ homeostasis is disrupted in VSMC, with decreased Ca2+ influx, smaller concentrations of Ca2+ in the sarcoplasmic reticulum, and decreased activation of Orai1. Abnormal Ca2+ handling contributes to LPS-associated vascular hyporeactivity.
AB - We hypothesized that SIRS/endotoxemia-associated hyporesponsiveness to vasoconstrictors is mediated by smaller increases in intracellular Ca2+ levels due to reduced signaling via the STIM/Orai. Male Wistar rats were injected either with saline or bacterial LPS (i.p.; 10 mg/kg), and experiments were performed 24 h later. LPS-injected rats exhibited decreased systolic blood pressure, increased heart rate, neutrophils’ migration into the peritoneal cavity, and elevated alanine aminotransferase levels. Additionally, second-order mesenteric arteries from endotoxemic rats displayed hyporeactivity to contractile agents such as phenylephrine and potassium chloride; decreased contractile responses to Ca2+; reduced contraction during Ca2+ loading; and smaller intracellular Ca2+ stores. Decreased Orai1, but not STIM1, expression was found in resistance mesenteric arteries from LPS-treated rats. Additionally, cultured vascular smooth muscle cell (VSMC) treated with LPS resulted in increased TLR-4 expression, but Myd-88 and STIM-1 expression were not changed. Our data suggest that in endotoxemia, Ca2+ homeostasis is disrupted in VSMC, with decreased Ca2+ influx, smaller concentrations of Ca2+ in the sarcoplasmic reticulum, and decreased activation of Orai1. Abnormal Ca2+ handling contributes to LPS-associated vascular hyporeactivity.
KW - calcium homeostasis
KW - hypotension
KW - vascular reactivity
KW - vascular smooth muscle cell
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U2 - 10.1007/s10753-016-0354-y
DO - 10.1007/s10753-016-0354-y
M3 - Article
C2 - 27099074
AN - SCOPUS:84964319083
SN - 0360-3997
VL - 39
SP - 1188
EP - 1197
JO - Inflammation
JF - Inflammation
IS - 3
ER -