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Calcium Signaling Dysregulation in Diabetic Cardiomyopathy: Roles of STIM and Orai Channels
Tarik Smani1,2, Beltzane Dominguez-Liste3,4, Marta de Jesús Gutiérrez-Barranco3,4
1Group of Cardiovascular Pathophysiology, Institute of Biomedicine of Seville, University Hospital of Virgen del Rocio/University of Seville/CSIC, Seville, Spain. tasmani@us.es.
Abstract:
Diabetes mellitus is a major metabolic disorder that significantly increases the risk of cardiovascular disease. Altered calcium (Ca2+) homeostasis, particularly through store-operated calcium entry (SOCE), has emerged as a critical pathway linking diabetes with cardiac dysfunction. Evidence indicates that SOCE is dysregulated in diabetes, but findings remain controversial. Some studies report reduced SOCE due to downregulation or impaired coupling of STIM1 and Orai1, leading to altered Ca2+ homeostasis and cardiac dysfunction. Others demonstrate enhanced SOCE linked to Orai and STIM isoforms upregulation, contributing to mitochondrial dysfunction, maladaptive hypertrophy, and metabolic remodeling in diabetic cardiomyopathy. Recent work also highlighted an unexpected role of STIM1 in fatty acid metabolism, linking Ca2+ signaling with energy substrate preference in the diabetic heart. This chapter synthesizes current evidence on the molecular mechanisms of STIM and Orai proteins in the regulation of SOCE under diabetic conditions, highlighting their roles in heart dysfunction.
Insights
Diabetes disrupts calcium signaling in the heart, impacting store-operated calcium entry (SOCE) via STIM and Orai proteins. This dysregulation contributes to diabetic cardiomyopathy and altered cardiac metabolism.
Area of Science:
- Cardiovascular Biology
- Metabolic Disorders
- Calcium Signaling
Background:
- Diabetes mellitus significantly elevates cardiovascular disease risk.
- Altered calcium (Ca2+) homeostasis, specifically store-operated calcium entry (SOCE), is implicated in diabetic cardiac dysfunction.
- The precise role of SOCE in diabetes remains controversial, with conflicting reports on its regulation.
Purpose of the Study:
- To synthesize current evidence on STIM and Orai proteins in regulating SOCE in diabetes.
- To elucidate the molecular mechanisms linking calcium signaling to cardiac dysfunction in diabetic conditions.
- To highlight the role of STIM/Orai in metabolic remodeling and fatty acid metabolism in the diabetic heart.
Main Methods:
- Literature review and synthesis of existing research on SOCE, STIM, and Orai proteins in diabetes.
- Analysis of studies investigating calcium homeostasis in diabetic cardiomyopathy.
- Examination of evidence linking STIM1 to fatty acid metabolism in the diabetic heart.
Main Results:
- SOCE dysregulation in diabetes is supported by conflicting findings: some studies show reduced SOCE (STIM1/Orai1 downregulation), while others report enhanced SOCE (isoform upregulation).
- Dysregulated SOCE contributes to altered Ca2+ homeostasis, mitochondrial dysfunction, maladaptive hypertrophy, and metabolic remodeling in diabetic cardiomyopathy.
- STIM1 plays a role in fatty acid metabolism, connecting Ca2+ signaling to energy substrate preference in the diabetic heart.
Conclusions:
- STIM and Orai proteins are critical regulators of SOCE, and their dysregulation is a key factor in diabetic cardiac dysfunction.
- Understanding these calcium signaling pathways is crucial for developing therapeutic strategies for diabetic cardiomyopathy.
- Further research is needed to fully reconcile the conflicting findings and elucidate the complex interplay between calcium homeostasis and metabolism in diabetes.
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