Key result
Treg-specific STIM1 deletion protects mice against stress-induced HFpEF by preventing diastolic dysfunction, hypertension, and fibrosis.
Why the study?
The mechanisms driving Treg dysfunction and the role of STIM1-dependent calcium signaling in Treg maladaptation during HFpEF remain poorly defined.
Does Treg-specific STIM1 deletion prevent the development of cardiometabolic HFpEF features in a mouse model?
Does Treg-specific STIM1 deletion prevent the development of cardiometabolic HFpEF features in a mouse model?
STIM1-dependent stress signaling in regulatory T cells drives immune-mediated HFpEF progression, identifying Treg STIM1 as a potential therapeutic target.
STIM1-driven Treg dysfunction may fuel HFpEF inflammation; hypothesis-generating for targeted immune therapies.
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. 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. 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. 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.
No takes yet. Share an insight, caveat, or question.
Srinivas et al. (2026) studied Heart failure with preserved ejection fraction (HFpEF). Treg-specific STIM1 deletion vs. Wild-type/Littermate controls (Stim1 flox/flox) was evaluated on Development of HFpEF features (diastolic dysfunction, hypertension, cardiac fibrosis). Treg-specific deletion of STIM1 in mice protected against cardiometabolic stress-induced HFpEF, preventing diastolic dysfunction, hypertension, and cardiac fibrosis.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: