PHD2 Deletion in CD8+ T Cells Worsens TAC-Induced Cardiac Inflammation, Heart Failure, and Pulmonary Remodeling

Abstract

Background: Cardiac inflammation is a key driver of cardiac fibrosis and heart failure. Cytotoxic CD8⁺ T cells play important roles in modulating inflammatory responses, especially during infections and autoimmune diseases. HIFs (hypoxia-inducible factors) regulate CD8⁺ T cell function and cardiac remodeling. However, the role of HIF in CD8⁺ T cells during heart failure development remains unclear.

Methods: We generated CD8⁺ T cell-specific PHD2 (prolyl hydroxylase domain protein 2)-deficient mice (PHD2^CKO), in which HIF bioavailability is increased due to the loss of PHD2. PHD2^CKO and wild-type littermates were subjected to pressure overload via transverse aortic constriction. Cardiac function, inflammation, and CD8⁺ T cell responses were assessed. CD8⁺ T cell metabolism was analyzed using Seahorse assays to measure extracellular acidification rate and oxygen consumption rate. HIF1α and HIF2α protein levels were measured by Western blotting.

Results: Under baseline conditions, PHD2 deletion in CD8⁺ T cells had no effect on heart function or effector molecule expression. Following transverse aortic constriction, PHD2^CKO mice showed exacerbated cardiopulmonary inflammation, fibrosis, and dysfunction. These effects were associated with enhanced CD8⁺ T cell activation and cytokine production. In vitro, PHD2-deficient CD8⁺ T cells exhibited increased glycolysis (extracellular acidification rate), reduced oxidative phosphorylation (oxygen consumption rate), and elevated HIF1α-but not HIF2α-levels. Pharmacological inhibition of HIF1α, but not HIF2α, reversed these metabolic and functional changes.

Conclusions: PHD2 deletion in CD8⁺ T cells aggravates cardiopulmonary remodeling after pressure overload by enhancing CD8⁺ T cell activation and cytokine release via a HIF1α-dependent mechanism.

Keywords: cytokines; fibrosis; heart failure; hypoxia; mice.