T-Cell-Derived IFNγ Instructs ECM Crosslinking by Cardiac Fibroblasts Through LOXL3 in Experimental Cardiometabolic HFpEF.

CD4+ T-cell–derived IFNγ drives LOXL3-dependent ECM stiffening in cardiac fibroblasts, and disrupting this axis attenuates adverse remodeling and improves diastolic function in a murine cardiometabolic HFpEF model.

• Why it matters: HFpEF involves left ventricular stiffening and inflammation, but the immune–stromal mechanism linking T-cell activity to ECM crosslinking and functional diastolic impairment in cardiometabolic HFpEF is unclear.
• What they did: Using a murine 2-hit cardiometabolic HFpEF model (high-fat diet plus hypertension via L-nitro-arginine-methyl ester), the study assessed diastolic function by echocardiography and ECM mechanics by uniaxial tensile testing, with T-cell depletion, IFNγ knockout, lysyl oxidase inhibition, and CD4+ T-cell–fibroblast cocultures plus pathway testing.
• The result: ECM stiffness strongly correlated with impaired diastolic function, and CD4+ T-cell infiltration was required for fibroblast lysyl oxidase upregulation; genetic or pharmacological disruption of the IFNγ–HIF1α–LOXL3 axis attenuated adverse ECM remodeling and improved diastolic function.

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