STIM1-dependent treg dysfunction promotes cardiometabolic HFpEF: insights from patients and animal studies.
B, S., A, K., H, P., J, X., P, F., J, M., IE, M., NE, R., JM, H., & RL, B. (2026). STIM1-dependent treg dysfunction promotes cardiometabolic HFpEF: insights from patients and animal studies.. Cardiovascular diabetology. https://doi.org/10.1186/s12933-026-03253-6
B S, A K, H P, J X, P F, J M, et al. STIM1-dependent treg dysfunction promotes cardiometabolic HFpEF: insights from patients and animal studies.. Cardiovascular diabetology. 2026; doi: 10.1186/s12933-026-03253-6
B S, A K, H P, et al. STIM1-dependent treg dysfunction promotes cardiometabolic HFpEF: insights from patients and animal studies.[J]. Cardiovascular diabetology. 2026. DOI: 10.1186/s12933-026-03253-6.
@article{b2026,
author = {Srinivas B and Kiran A and Peng H and Xu J and Fortuno P and May J and Moudden IE and Rhaleb NE and Herre JM and Benza RL},
title = {STIM1-dependent treg dysfunction promotes cardiometabolic HFpEF: insights from patients and animal studies.},
journal = {Cardiovascular diabetology},
year = {2026},
doi = {10.1186/s12933-026-03253-6},
note = {PMID: 42421074},
}
TY - JOUR AU - Srinivas B AU - Kiran A AU - Peng H AU - Xu J AU - Fortuno P AU - May J AU - Moudden IE AU - Rhaleb NE AU - Herre JM AU - Benza RL TI - STIM1-dependent treg dysfunction promotes cardiometabolic HFpEF: insights from patients and animal studies. T2 - Cardiovascular diabetology PY - 2026 DO - 10.1186/s12933-026-03253-6 AN - PMID:42421074 ER -
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 (TregStim1-/-) 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, TregStim1-/- 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.