Abstract
Effective therapy of hypertension represents a key strategy for reducing the burden of cardiovascular disease and its associated mortality. The significance of voltage dependent L-type Ca²⁺ channels to Ca²⁺ influx, and of their regulatory mechanisms in the development of heart disease, is well established. A wide variety of L-type Ca²⁺ channel inhibitors and Ca²⁺ antagonists have been found to be beneficial not only in the treatment of hypertension, but also in myocardial infarction and heart failure. Over the past two decades, another class of Ca²⁺ channel - the voltage independent store-operated Ca²⁺ channel - has been implicated in the regulation and fine tuning of Ca²⁺ entry in both cardiac and smooth muscle cells. Store-operated Ca²⁺ channels are activated by the depletion of Ca²⁺ stores within the endoplasmic/sarcoplasmic reticulum, or by low levels of cytosolic Ca²⁺, thereby facilitating agonist-induced Ca²⁺ influx. Store-operated Ca²⁺ entry through this pivotal pathway involves both stromal interaction molecule (STIM) and Orai channels. Different degrees of changes in these proteins are considered to promote Ca²⁺ entry and hence contribute to the pathogenesis of cardiovascular dysfunction. Several blockers of store-operated Ca²⁺ channels acting at the level of both STIM and Orai channels have been shown to depress Ca²⁺ influx and lower blood pressure. However, their specificity, safety, and clinical significance remain to be established. Thus, there is an ongoing challenge in the development of selective inhibitors of store-operated Ca²⁺ channels that act in vascular smooth muscles for the improved treatment of hypertension.
Highlights
Significant improvements in the management and treatment of coronary heart disease and stroke have reduced overall cardiovascular mortality in recent decades, it remains the number one killer worldwide (Forouzanfar et al, 2017; Lawes et al, 2008; Wellman et al, 2001)
According to Global Health Observatory data, 1.13 billion people globally are affected with elevated blood pressure (BP), which increases morbidity of conditions such as left ventricular hypertrophy, coronary heart disease, heart failure, atrial fibrillation, and peripheral artery disease (Lewington et al, 2002; Manolis et al, 2015; Mrowka, 2019; Wei et al, 2017)
Knowledge is incomplete regarding the role of storeoperated calcium channels (SOCC) in the pathogenesis of cardiovascular disease
Summary
Significant improvements in the management and treatment of coronary heart disease and stroke have reduced overall cardiovascular mortality in recent decades, it remains the number one killer worldwide (Forouzanfar et al, 2017; Lawes et al, 2008; Wellman et al, 2001). In view of the critical role of Ca2+ in determining the status of cardiovascular function (Barlow et al, 2006; Bers, 2008; Berridge et al, 2000; Carafoli, 2003; Cortes et al, 1997; Dhalla et al, 1977, 1982), we describe the roles of various types of Ca2+ channels in health and disease, as well as therapeutic interventions that inhibit the vascular contractile response via blockage of Ca2+ entry into vascular smooth muscle. Treatments for hypertension include diuretics, betablockers, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, vasodilators, and calcium channel antagonists (Bhatt et al, 2014; Chobanian et al, 2003; Fleckenstein, 1977; Godfraind, 2017; Gong et al, 1996; Kuramoto, 1999; Liu et al, 1998; Ozawa et al, 2006; Staessen et al, 1997; Tocci et al, 2015). As such,efforts are being made to discover other types of Ca2+entry blockers acting upon voltage independent Ca2+-channels, which may confer fewer side effects (Collins et al, 2013; Colovina, 1999; Guibert et al, 2008; Leung et al, 2008; Xu et al, 2015)
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