STIM1-dependent treg dysfunction promotes cardiometabolic HFpEF: insights from patients and animal studies

Document Type

Article

Publication Date

7-8-2026

Publication Title

Cardiovascular diabetology

Keywords

Animals, T-Lymphocytes, Regulatory, Stromal Interaction Molecule 1, Humans, Stroke Volume, Disease Models, Animal, Mice, Knockout, Heart Failure, Male, Female, Mice, Inbred C57BL, Ventricular Function, Left, Endoplasmic Reticulum Stress, Aged, Calcium Signaling, Inflammation Mediators, Middle Aged, Apoptosis, Ventricular Remodeling, Fibrosis, Case-Control Studies, Interferon-gamma, Signal Transduction, Neoplasm Proteins

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.

Medical Subject Headings

Animals; T-Lymphocytes, Regulatory; Stromal Interaction Molecule 1; Humans; Stroke Volume; Disease Models, Animal; Mice, Knockout; Heart Failure; Male; Female; Mice, Inbred C57BL; Ventricular Function, Left; Endoplasmic Reticulum Stress; Aged; Calcium Signaling; Inflammation Mediators; Middle Aged; Apoptosis; Ventricular Remodeling; Fibrosis; Case-Control Studies; Interferon-gamma; Signal Transduction; Neoplasm Proteins

PubMed ID

42421074

Volume

25

Issue

1

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