Pulmonary arterial hypertension (PAH) is characterized by overgrowth of vascular cells, deposition of extracellular matrix and infiltration of inflammatory cells, challenging current available treatments. Immune dysregulation is recognized in the pathogenesis of PAH, e.g. PAH is a complication of connective tissue diseases (CTDs). Epigenetic mechanisms, such as histone acetylation, are emerging as key players in maintaining immune homeostasis. This thesis examines epigenetic regulation of the immune system by histone deacetylase (HDAC) inhibition in PAH.
We firstly demonstrated aberrant expressions of class II HDACs along with decreased circulating regulatory T (Treg) cells in the peripheral blood mononuclear cells (PBMCs) from idiopathic PAH patients. Follow on ex vivo experiment showed that broad spectrum HDAC inhibition by suberoylanilide hydroxamic acid (SAHA) treatment in isolated CD4+CD25- conventional T cells induced significantly higher Foxp3 expression and Treg conversion in the cells from idiopathic PAH patients compared with healthy donors.
I established the first autoimmune disorder associated pulmonary hypertension (PH) rat model, the R-SU PH model. This model demonstrates severe PH and recapitulates important pathology of human PAH including complex pulmonary vascular remodeling with exaggerated perivascular inflammation in addition to multi-system autoimmune conditions, including glomerulonephritis and massive splenomegaly. This model will be valuable for exploring the impact of autoimmunity in the pathogenesis of PAH. It can be employed specifically as a preclinical model for studying targeted treatment for CTD associated PAH.
Aberrant expressions of HDACs and decreased circulating Treg cells in the PBMCs were recapitulated by PH animal models, including the R-SU rat model. Treatment of SAHA restored Treg activity and suppressed inflammatory responses in the lung, attenuating the PH phenotypes in three PH rodent models.
My results demonstrated that immune dysregulation is involved in the development of PAH pathology. HDAC inhibitor SAHA modulates immune homeostasis and has the therapeutic potential for PAH.