Essential role of Orai1 and SARAF in vascular remodeling

Abstract

Orai1 and STIM1, molecular components of store-operated calcium entry (SOCE), have been associated with vascular smooth muscle cell (VSMC) proliferation in vascular remodeling. Nevertheless, the role of SARAF (SOCE-associated regulatory factor), a regulatory protein involved in STIM1 inhibition, in vascular remodeling has not been examined. The aim of this study is to examine the role of SARAF and Orai1 in VSMC proliferation and neointima formation after balloon injury of rat carotid arteries. Experiments were conducted in an animal model of rat carotid angioplasty to characterize neointima formation. VSMC isolated from rat coronary arteries was also used to examine cell proliferation. The formation of neointima after balloon injury of rat carotid arteries was confirmed by hematoxylin and eosin staining of tissue sections up to 3 wk after surgery. Injured arteries showed significantly higher expression of SARAF, STIM1, and Orai1 compared with control tissues, corroborating the presence of these regulatory proteins in the neointima layer. Proximity ligation and coimmunoprecipitation assays revealed that SARAF interacts with Orai1 in the neointima. Furthermore, selective silencing of SARAF and Orai1 by small interfering RNA (siRNA) inhibited IGF-1–induced VSMC proliferation. Our data suggest that SARAF interacts with Orai1 to modulate SOCE and VSMC proliferation after vascular injury.

STIM and Orai Mediated Regulation of Calcium Signaling in Age-Related Diseases

“…It was recently shown that the expression of SARAF was increased in balloon injured arteries along with STIM1 and Orai1. SARAF was shown to specifically regulate Orai1-mediated VMSC proliferation in response to balloon injury ( Martin-Bornez et al, 2022 ). Homer has also been shown to colocalize with STIM1/Orai1 and regulate Orai1-mediated VSMC proliferation and neointimal growth in the setting of balloon injured arteries ( Jia et al, 2017 ).…”