QKI Promotes Hypoxia Induced Smooth Muscle Reprogramming in Pulmonary Hypertension

Abstract Background: Pulmonary hypertension (PH) is a complex and progressive cardiopulmonary disorder with poor prognosis and limited therapeutic treatments. Recent evidence suggests that RNA binding proteins (RBPs) participate in the pathogenesis of human and experimental pulmonary arterial hypertension. Quaking (QKI) as an important RBPs is involved in mRNA biogenesis, export, decay and translation. However, the biological significance of QKI in phenotypic transformation of PASMCs in PH as well as in abnormal pulmonary vascular remodeling remain elusive. Methods: We assessed the expression pattern, phenotypic transformation effect, and mechanism of QKI in rodent Su/Hx-induced PH model, Human PAH samples and in HPASMCs. Results: Elevated protein expression level of QKI was found in animal PH and human PAH samples, thus in hypoxic HPASMCs. Inhibition of QKI attenuated proliferation and phenotype switching in HPASMCs. Mechanistically, QKI was found to mediate STAT3 mRNA stabilization by binding to its 3’Untranslated Region (3’-UTR). Downregulation of QKI attenuated STAT3 expression in PASMCs, while overexpression of STAT3 in PASMCs was widely regarded to be involved in the progression of PH. In addition, as a transcription factor, STAT3 was identified to bound to miR-146b promoter to induce its expression, while miR-146b was proved to promote smooth muscle reprogramming through inhibiting STAT1 and TET2 expression during pulmonary vascular remodeling. Conclusions: Our study demonstrates the QKI-STAT3-miR-146b pathway as a novel mechanistic insights into hypoxic reprogramming that permits vascular remodeling, and thus provides proof of concept for anti-remodeling therapy through the direct modulation this axis in PH.