ORAI1 Ca2+ channel as a therapeutic target in pathological vascular remodelling

Cardiovascular disease (CVD) defines the conditions affecting the heart and blood vessels. CVD is currently the leading cause of global mortality, accounting for an estimated 17 million deaths annually (WHO, 2017). This figure is anticipated to rise as the prevalence in low and middle-income countries increases. CVD is associated with classical risk factors, including obesity (Poirier et al., 2006), smoking (Keto et al., 2016), family history (Dorairaj and Panniyammakal, 2012; Jeemon et al., 2017), and diabetes (Rydén et al., 2013; Shah et al., 2015). Atherosclerotic CVD (e.g., ischaemic heart disease, peripheral arterial disease, cerebrovascular disease, renovascular disease), pulmonary hypertension and aneurysm formation have all been associated with pathological remodelling behaviour of the native vascular smooth muscle cells (VSMC) within the arterial wall. Similarly, failure of surgical revascularisation to treat atherosclerotic CVD lesions (bypass grafting with autologous vein or prosthetic graft) or percutaneous coronary intervention/peripheral artery endovascular intervention (angioplasty+/−stenting) is associated with neointimal hyperplasia (NIH) which is also a manifestation of pathological vascular remodelling. The ability to selectively inhibit such pathological remodelling of VSMC is therefore considered to be a potentially fruitful therapeutic strategy across this range of cardiovascular pathologies. In order to achieve this, an identifiable, specific, druggable target is required. In this review we present an update on the evidence supporting the ORAI1 Ca2+ channel as a potential therapeutic target and the current status of inhibitor development. The focus is on atherosclerotic CVD and NIH as little evidence exists regarding aneurysm disease in this context and we recently reviewed the evidence supporting ORAI1 as a target in pulmonary hypertension (Rode et al., 2018).