The constitutive function of native TRPC3 channels modulates vascular cell adhesion molecule-1 expression in coronary endothelial cells through nuclear factor kappaB signaling.
نویسندگان
چکیده
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.
منابع مشابه
The Constitutive Function of Native TRPC3 Channels Modulates Vascular Cell Adhesion Molecule-1 Expression in Coronary Endothelial Cells Through Nuclear Factor B Signaling
متن کامل
Involvement of native TRPC3 proteins in ATP-dependent expression of VCAM-1 and monocyte adherence in coronary artery endothelial cells.
UNLABELLED Background- Vascular cell adhesion molecule-1 (VCAM-1) is critical in monocyte recruitment to the endothelium, a key event in development of atherosclerotic lesions. Stimulation of human coronary artery endothelial cells (HCAECs) with ATP positively modulates VCAM-1 expression and function through a mechanism involving Ca(2+) signaling. We here examined the role of Ca(2+) influx and ...
متن کاملThe effect of microRNA-125 on the adhesion molecule expression of integrin beta2 and adhesive determination of endothelial cells isolated from human aorta to monocyte
Background: The immune-mediated responses in vascular cells may include the increased expression of endothelial adhesion molecules, leukocyte rolling and infiltration, cellular lipid dysregulation and vascular smooth muscle cells (VSMCs) differentiation. Investigating the cellular and molecular events involved in the rolling process is useful for treatment or prevention of the vessel stenosis es...
متن کاملIncreased size and cellularity of advanced atherosclerotic lesions in mice with endothelial overexpression of the human TRPC3 channel.
In previous in vitro studies, we showed that Transient Receptor Potential Canonical 3 (TRPC3), a calcium-permeable, nonselective cation channel endowed with high constitutive function, is an obligatory component of the inflammatory signaling that controls expression of the vascular cell adhesion molecule-1 (VCAM-1) and monocyte adhesion to coronary artery endothelial cells. Also, TRPC3 expressi...
متن کاملRadiation-induced expression of platelet endothelial cell adhesion molecule-1 in cerebral endothelial cells
Background: Radiation-induced molecular changes on the endothelial surface of brain arteriovenous malformations (AVM) may be used as markers for specific vascular targeting agents. In this study, we examined the level of expression of platelet endothelial cell adhesion molecule-1 (PECAM-1) on brain endothelial cell surface after radiation treatment, with the aim of targeting the radiation-induc...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
عنوان ژورنال:
- Circulation research
دوره 106 9 شماره
صفحات -
تاریخ انتشار 2010