ORAI1 Ca2+ Channel as a Therapeutic Target in Pathological Vascular Remodelling

Abstract

In the adult, vascular smooth muscle cells (VSMC) are normally physiologically quiescent, arranged circumferentially in one or more layers within blood vessel walls. Remodelling of native VSMC to a proliferative state for vascular development, adaptation or repair is driven by platelet-derived growth factor (PDGF). A key effector downstream of PDGF receptors is store-operated calcium entry (SOCE) mediated through the plasma membrane calcium ion channel, ORAI1, which is activated by the endoplasmic reticulum (ER) calcium store sensor, stromal interaction molecule-1 (STIM1). This SOCE was shown to play fundamental roles in the pathological remodelling of VSMC. Exciting transgenic lineage-tracing studies have revealed that the contribution of the phenotypically-modulated VSMC in atherosclerotic plaque formation is more significant than previously appreciated, and growing evidence supports the relevance of ORAI1 signalling in this pathologic remodelling. ORAI1 has also emerged as an attractive potential therapeutic target as it is accessible to extracellular compound inhibition. This is further supported by the progression of several ORAI1 inhibitors into clinical trials. Here we discuss the current knowledge of ORAI1-mediated signalling in pathologic vascular remodelling, particularly in the settings of atherosclerotic cardiovascular diseases (CVDs) and neointimal hyperplasia, and the recent developments in our understanding of the mechanisms by which ORAI1 coordinates VSMC phenotypic remodelling, through the activation of key transcription factor, nuclear factor of activated T-cell (NFAT). In addition, we discuss advances in therapeutic strategies aimed at the ORAI1 target.

Role of Store-Operated Ca2+ Entry in the Pulmonary Vascular Remodeling Occurring in Pulmonary Arterial Hypertension

“…Concerning inhibitors of Orai1, there is a well-known family of pyrazole derivatives, with the widely used BTP2 (YM-58483) [ 214 , 215 , 216 , 217 , 218 ] and GSK compounds (GSK7975A and GSK-5503A) [ 220 ], acting on the selectivity filter of Orai1, Synta-66, which binds directly to Orai1 [ 221 , 222 , 223 , 224 ] and its suitable in vivo analogue JPIII [ 225 ]. The lanthanide family (Gd 3+ or La 3+ ) has been known as an Orai blocker for many years [ 219 , 226 ].…”

ORAI Calcium Channels: Regulation, Function, Pharmacology, and Therapeutic Targets

“…A separate study by Zhang et al showed that GSK7975A largely inhibits Orai1 and Orai2 while it has a lower inhibitory effect against Orai3 [ 72 ]. As GSK7975A is unable to discriminate between Orai1 and Orai3 channels, as well as lacking the ability to block L-type Ca 2+ and TRPV6 channels, the compound has a limited specificity as an Orai1 channel blocker [ 23 ].…”

“…Somatic cell migration and proliferation (SOCE) mediated by Orai1 are related with the stimulation of the nuclear factor of the activated T-cell (NFAT), which increases the proliferation and migration of VSMCs. Additionally, Ca 2+ influx through Orai1 stimulates mitochondrial Ca 2+ uptake through the mitochondrial Ca 2+ uniporter [ 23 ].…”

CRACking the Molecular Regulatory Mechanism of SOCE during Platelet Activation in Thrombo-Occlusive Diseases

“…In particular, molecular targets that do not, or only mildly affect bleeding times, are promising candidates for improved future anti-platelet and antithrombotic treatment regimens. While there is a plurality of SOCE interfering compounds which are well summarized by Shawer et al [ 113 ], only inhibitors of SOCE compounds described in platelets and thrombus formation are briefly described here.…”

“…Moreover, in vivo administration of SKF-96365 leads to a significantly reduced atherosclerotic plaque progression in a mouse model using apolipoprotein E knockout mice [ 120 ]. However, comparable with 2-APB, the effect of SKF-96365 on platelet function and atherothrombosis cannot be clearly linked with the SOCE machinery in platelets, since a lot of other ion channels are reported to be affect by SKF-96365 [ 113 ]. Amongst others, work by Derler and colleagues in 2013 identified GSK-7975 A as a pore-forming blocking compound of Orai-mediated SOCE [ 121 ].…”