T Hücresi Kaynaklı IFNγ, Deneysel Kardiyometabolik HFpEF'de LOXL3 Aracılığıyla Kardiyak Fibroblastların ECM Çapraz Bağlanmasını Yönlendirir

Özet (abstract)

Abstract Background Heart failure with preserved ejection fraction (HFpEF) is a major clinical challenge characterized by diastolic dysfunction. Left ventricular stiffening and inflammation are hallmarks of HFpEF, yet the contribution of extracellular matrix (ECM) stiffness and the immune–stromal mechanisms driving ECM stiffening in cardiometabolic HFpEF remain poorly understood. Methods We used the murine “2-hit model” of cardiometabolic HFpEF, in which the combination of high fat diet and hypertension induced by L-NAME causes diastolic dysfunction. We evaluated diastolic function by echocardiography and ECM mechanics by uniaxial tensile testing of decellularized cardiac tissue. Functional in vivo studies included genetic depletion of T cells, interferon-γ (IFNγ) knockout mice, and pharmacological lysyl oxidase inhibition. We combined co-cultures of CD4 + T cells and cardiac fibroblasts (CFB) with mechanical testing of cardiac ECM and molecular biology to elucidate cellular and molecular mechanisms. Results Left ventricular ECM stiffness strongly correlated with impaired diastolic function in experimental cardiometabolic HFpEF. Cardiac CD4⁺ T cell infiltration was required for ECM stiffening and upregulation of lysyl oxidase enzymes in CFB. CD4 + T cell-derived IFNγ was both necessary and sufficient to induce LOXL3 in CFB, which increased ECM stiffness in vitro . Mechanistically, IFNγ signaling activated hypoxia-inducible factor-1α (HIF1α) in CFB, driving LOXL3 expression and subsequent collagen crosslinking. Genetic or pharmacologic disruption of this IFNγ–HIF1α–LOXL3 axis in vivo attenuated adverse ECM remodeling and improved diastolic function. Conclusions CD4⁺ T cells promote pathological ECM stiffening in cardiometabolic HFpEF through IFNγ-mediated, LOXL3-dependent ECM crosslinking by CFB. Targeting this immune–stromal pathway may offer a novel therapeutic strategy for HFpEF.

Yazarların özeti; kaynağından alınmıştır. Circulation Research, 2026 · DOI ↗