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The constitutive function of native TRPC3 channels modulates vascular cell adhesion molecule-1 expression in coronary endothelial cells through nuclear factor kappaB signaling.

Abstract：

RATIONALE:Upregulation of endothelial vascular cell adhesion molecule (VCAM)-1 and the subsequent increase in monocyte recruitment constitute critical events in atherogenesis. We have recently shown that in human coronary artery endothelial cells (HCAECs) regulated expression of VCAM-1 depends, to a significant extent, on expression and function of the Ca(2+)-permeable channel transient receptor potential canonical (TRPC)3, regardless of the ability of the stimulatory signal to induce regulated Ca(2+) influx, leading to the hypothesis that TRPC3 constitutive, rather than regulated function, contributes to the underlying signaling mechanism. OBJECTIVE:The present studies addressed this important question and gathered mechanistic insight on the signaling coupling constitutive TRPC3 function to VCAM-1 expression. METHODS AND RESULTS:In HCAECs, maneuvers that prevent Ca(2+) influx or knockdown of TRPC3 markedly reduced tumor necrosis factor (TNF)alpha-induced VCAM-1 and monocyte adhesion. TNFalpha also induced TRPC3 expression and TRPC3-mediated constitutive cation influx and currents. Stable (HEK293 cells) or transient (HCAECs) overexpression of TRPC3 enhanced TNFalpha-induced VCAM-1 compared to wild-type cells. IkappaBalpha phosphorylation/degradation was reduced by TRPC3 knockdown and increased by channel overexpression. Inhibition of calmodulin completely prevented nuclear factor kappaB activation, whereas blocking calmodulin-dependent kinases or NADPH oxidases rendered partial inhibition. CONCLUSIONS:Our findings indicate that in HCAECs expression of VCAM-1 and monocyte adhesion depend, to a significant extent, on TRPC3 constitutive function through a signaling mechanism that requires constitutive TRPC3-mediated Ca(2+) influx for proper activation of nuclear factor kappaB, presumably through Ca(2+)-dependent activation of the calmodulin/calmodulin-dependent kinase axis.

journal_name

Circ Res

journal_title

Circulation research

authors

Smedlund K,Tano JY,Vazquez G

doi

10.1161/CIRCRESAHA.109.213314

subject

Has Abstract

pub_date

2010-05-14 00:00:00

pages

1479-88

issue

eissn

0009-7330

issn

1524-4571

pii

CIRCRESAHA.109.213314

journal_volume

106

pub_type

杂志文章

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The constitutive function of native TRPC3 channels modulates vascular cell adhesion molecule-1 expression in coronary endothelial cells through nuclear factor kappaB signaling.