STIM1-Dependent Treg Dysfunction Promotes Cardiometabolic HFpEF: Insights from Patients and Animal Studies

Authors

• Balaji Srinivas, Macon & Joan Brock Virginia Health Sciences at Old Dominion University
• Alluri Kiran, Macon & Joan Brock Virginia Health Sciences at Old Dominion University
• Hongmei Peng, Wayne State University
• Jiang Xu, Wayne State University
• Paula Fortuno, Macon & Joan Brock Virginia Health Sciences at Old Dominion University
• Jennifer May, Sentara Health Research Center
• Ismail El Moudden, Macon & Joan Brock Virginia Health Sciences at Old Dominion UniversityFollow
• Nour-Eddine Rhaleb, Wayne State University
• John M. Herre, Sentara Norfolk General Hospital
• Raymond L. Benza, Macon & Joan Brock Virginia Health Sciences at Old Dominion UniversityFollow
• Khalid Matrougui, Macon & Joan Brock Virginia Health Sciences at Old Dominion UniversityFollow

ORCID

0009-0007-1567-3434 (Alluri), 0000-0001-7702-2564 (El Moudden), 0000-0001-9627-6236 (Benza),

Document Type

Article

Publication Date

2026

DOI

10.1186/s12933-026-03253-6

Publication Title

Cardiovascular Diabetology

Volume

25

Issue

1

Pages

197

Abstract

Background

Heart failure with preserved ejection fraction (HFpEF) arises from chronic cardiometabolic and vascular stress and is increasingly recognized as an inflammatory syndrome with immune dysregulation. Regulatory T cells (Tregs) are critical modulators of cardiovascular inflammation, yet the mechanisms driving Treg dysfunction in HFpEF remain poorly defined. stromal interaction molecule 1 (STIM1)-dependent calcium signaling is a key stress-responsive pathway in immune cells; however, its role in Treg maladaptation during HFpEF remains unknown.

Methods

Circulating Tregs from patients with and without HFpEF were analyzed for abundance, STIM1 expression, and stress-associated signaling pathways. To establish causality, mice with Treg-specific deletion of STIM1 (Treg^Stim1-/-) and littermate controls were subjected to a high-fat diet and nitric oxide synthase inhibition (L-NAME) to induce a cardiometabolic HFpEF model. Cardiac diastolic function, vascular reactivity, blood pressure, and exercise capacity were assessed alongside structural remodeling.

Results

Patients with HFpEF exhibited reduced circulating Treg numbers accompanied by increased STIM1 expression and activation of apoptotic, inflammatory, and ER stress pathways, consistent with stress-induced Treg instability. In vivo, control mice developed features of HFpEF, including diastolic dysfunction with preserved ejection fraction, hypertension, metabolic dysregulation, endothelial dysfunction, cardiac fibrosis, and impaired exercise tolerance. In contrast, Treg^Stim1-/- mice were protected from these abnormalities. Mechanistically, STIM1 signaling promoted loss of Treg suppressive stability and the acquisition of effector-like inflammatory signaling, including IL-17- and IFN-γ-dependent cardiomyocyte activation, whereas STIM1-deficient Tregs maintained a non-pathogenic phenotype.

Conclusions

STIM1-dependent stress signaling drives maladaptive Treg instability that amplifies cardiovascular inflammation and HFpEF progression. These findings identify Treg STIM1 as a key driver of immune-mediated HFpEF progression and provide mechanistic evidence from humans to mice supporting immune-targeted therapeutic strategies.

Rights

© The Authors 2026.

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Data Availability

Article states: "Data are available upon reasonable request."

Original Publication Citation

Srinivas, B., Kiran, A., Peng, H., Xu, J., Fortuno, P., May, J., Moudden, I. E., Rhaleb, N. E., Herre, J. M., Benza, R. L., & Matrougui, K. (2026). STIM1-dependent treg dysfunction promotes cardiometabolic HFpEF: Insights from patients and animal studies. Cardiovascular Diabetology, 25(1), Article 197. https://doi.org/10.1186/s12933-026-03253-6

Repository Citation

Srinivas, B., Kiran, A., Peng, H., Xu, J., Fortuno, P., May, J., Moudden, I. E., Rhaleb, N. E., Herre, J. M., Benza, R. L., & Matrougui, K. (2026). STIM1-dependent treg dysfunction promotes cardiometabolic HFpEF: Insights from patients and animal studies. Cardiovascular Diabetology, 25(1), Article 197. https://doi.org/10.1186/s12933-026-03253-6