The role of nuclear factor of activated T cells in pulmonary arterial hypertension

Figures & data

Figure 1. The mechanisms of NFATc2 promote PAH. Pro-PAH factors increase STAT3 phosphorylation. Then phosphorylated STAT3 translocates into nucleus and increases NFATc2 and Pim-1 expression. Pim-1 triggers NFATc2 dephosphorylation and nuclear translocation and Bad phosphorylation, which inhibits kv1.5 expression and promotes Bcl2 expression. Aerobic glycolysis inhibits GSK3β activation, which increases the nuclear localization of NFATc2. downregulation of kv1.5 results in increase of [Ca²⁺]i and [K+]i. Upregulated Bcl2 hyperpolarizes mitochondrial membrane potential(ΔΨm) and lowers mitochondrial ROS. Meantime, NFATc2 binding with DNA also enhances cyclin A expression and in turn promotes CDK2 activation. CDK2 activation and [Ca²⁺]i increase results in PASMC proliferation. Elevated [K+]i together with decreased ΔΨm and mROS inhibits PASMC apoptosis. Finally, the hyperproliferative and anti-apoptotic diathesis within the resistance pulmonary arterial wall lead to vascular remodeling and a progressive increase in pulmonary vascular resistance.

Figure 2. NFATc3 involves in PASMC hypertrophy and proliferation. Endothelial dysfunction induced by hypoxia upregulates the expression of TRPC1 and STIM1 in PASMC, which in turn induces SOC-mediated [Ca²⁺] influx and subsequent activation of calcineurin phosphatase activity and accumulation of NFATc3 in the nucleus. Once activated, NFATc3 could induce the transcription of TRPC1 in a positive feedback manner. ET-1 induced by hypoxia stimulates RhoA/ROK activity, which promotes nucleus translocation of NFATc3. Once NFATc3 translocates into nucleus, it may upregulate α-SMA in PASMC and in turn promotes PASMC hypertrophy. Moreover, NFATc3 also involves in proliferation of PASMC. PASMC hypertrophy and proliferation results in thickening of the pulmonary artery wall and remodeling.