Loading
Hypertension / Cardiovascular Disease / Cardiovascular Diseases · Journal article
Channels · July 26, 2026
Raises a question worth testing. It does not answer one.
This narrative review examines the molecular mechanisms by which STIM1/2 and Orai1/3 proteins regulate store-operated calcium entry (SOCE) and their putative roles in cardiovascular pathophysiology, including hypertension, atherosclerosis, and cardiac remodeling. The authors emphasize regulatory complexity beyond the canonical STIM–Orai axis, note the functional heterogeneity of Orai1 (protective in adult myocardium but pro-hypertrophic in neonatal cells), and identify translational barriers—poor isoform selectivity, inadequate pharmacokinetics, and lack of biomarkers—that have prevented clinical deployment of SOCE inhibitors to date.
Narrative review. Cardiovascular disease patients in whom SOCE dysregulation occurs; preclinical work in cardiomyocytes (adult and neonatal), vascular smooth muscle, and platelets..
STIM1/2 activate plasma membrane Orai1/3 channels upon ER Ca2+ store depletion, initiating Ca2+ entry that drives vasoconstriction, smooth muscle proliferation, platelet activation, and cardiac hypertrophy. Dysregulated SOCE is associated with hypertension, atherosclerosis, pulmonary hypertension, and thromboembolic disorders. Orai1 exerts a protective role in adult cardiomyocytes but promotes hypertrophy and remodeling under specific pathological conditions, posing a therapeutic dilemma.
Clinical translation of SOCE inhibitors remains hindered by poor isoform selectivity, suboptimal pharmacokinetics, lack of tissue-specific delivery, disease-stage-dependent effects, and absence of validated biomarkers.
This review does not establish that any therapeutic intervention targeting SOCE is ready for clinical use. It underscores that despite strong preclinical rationale, SOCE inhibitors have not yet overcome selectivity, pharmacokinetic, and biomarker challenges needed for evidence-based clinical translation in hypertension, atherosclerosis, or cardiac disease.
This is a narrative review synthesizing mechanistic understanding of STIM/Orai-mediated calcium signaling in cardiovascular disease, raising therapeutic questions rather than reporting new empirical evidence or answering them with clinical trials.
As stated by the source record.
Quoted from the source exactly as published.
This review does not establish that any therapeutic intervention targeting SOCE is ready for clinical use. It underscores that despite strong preclinical rationale, SOCE inhibitors have not yet overcome selectivity, pharmacokinetic, and biomarker challenges needed for evidence-based clinical translation in hypertension, atherosclerosis, or cardiac disease.
Graded across the dimensions that decide whether you should act, each from what the source actually supports. There is no single score, and where a dimension was not assessed it says so.
Store-operated calcium entry (SOCE) mediated by STIM and Orai proteins is a fundamental Ca2+ influx mechanism that critically regulates intracellular calcium homeostasis and participates in cardiovascular pathophysiology. Upon endoplasmic reticulum Ca2+ store depletion, STIM1/2 activate plasma membrane Orai1/3 channels, initiating Ca2+ entry that drives vasoconstriction, smooth muscle proliferation, platelet activation, and cardiac hypertrophy. Dysregulated SOCE is closely associated with hypertension, atherosclerosis, pulmonary hypertension, and thromboembolic disorders. However, SOCE is not a simple binary pathway but operates within a complex regulatory network. Beyond the core STIM-Orai axis, auxiliary proteins including transient receptor potential canonical 1 (TRPC1), tetraspanin 18 (Tspan18), tropomyosin 3 (TPM3), SOCE-associated regulatory factor (SARAF), and A-kinase anchoring protein 79/150 (AKAP79/150) modulate SOCE amplitude, kinetics, and downstream signaling in a cell- and context-dependent manner. Moreover, the functional consequences of SOCE are highly heterogeneous: Orai1 protects adult cardiomyocytes but promotes pathological hypertrophy in neonatal cells, posing a therapeutic dilemma. Although preclinical studies have shown efficacy of SOCE inhibitors, clinical translation remains hindered by poor isoform selectivity, suboptimal pharmacokinetics, lack of tissue-specific delivery, disease-stage-dependent effects, and absence of validated biomarkers. Importantly, recent evidence has definitively ruled out amlodipine-induced CRAC channel activation at therapeutic concentrations, confirming it as an experimental artifact. This review systematically summarizes the molecular complexity, functional diversity, and translational barriers of STIM/Orai-mediated SOCE, aiming to inform precision therapeutic strategies for cardiovascular diseases.
Taken from the source record, never inferred. Follow any of these and new work involving them reaches your briefing.