Abstract Body: Background: Prolyl hydroxylase domain proteins (PHD) are oxygen-sensing molecules that degrade hypoxia-inducible factor-α. Deletion of endothelial-specific PHD2 (PHD2ECKO) shows different degrees of pulmonary arterial hypertension and cardiac hypertrophy. Whether EC-specific PHD2 deletion plays a role in regulating cardiac inflammation and dysfunction is still unclear. We investigated the effect of endothelial-specific PHD2 deficiency on cardiac inflammation and dysfunction in mice.
Methods: Briefly, PHD2ECKO mice were obtained by crossing PHD2-floxed mice with VE-Cadherin-Cre transgenic mice. The effect of PHD2ECKO on cardiac structure and function was determined in male young (6 months old) and old (12-16 months old) mice.
Results: While PHD2ECKO caused significant left ventricular (LV) hypertrophy in mice at 6 months, PHD2ECKO had no significant impact on LV fibrosis and dysfunction in these mice. However, PHD2ECKO caused significant LV leukocyte infiltration, fibrosis, cardiomyocyte hypertrophy, and LV dysfunction in mice over 12 months. Most interestingly, we found that PHD2ECKO caused a significant increase of cardiac CD4⁺ T cells and CD8⁺ T cells, activation, and their proinflammatory cytokine productions in mice at the age of 12 months. Moreover, we found that PHD2ECKO resulted in a significant upregulation of several adhesion molecules important for CD4⁺ and CD8⁺ T cell homing, retention, and proliferation. However, the cytokine production by other immune cell subsets was largely unaffected.
Conclusions: Our findings demonstrated that endothelial-PHD2 exerts an important role in proliferation, activation, and proinflammatory cytokine production by CD4 and CD8 T cells, and the aging-dependent LV hypertrophy and dysfunction.