Circ‐myh8 Promotes Pulmonary Hypertension by Recruiting KAT7 to Govern Hypoxia‐Inducible Factor‐1α Expression

Abstract

Background Aberrant expression of circular RNAs (circRNAs) contributes to the initiation and progression of pulmonary hypertension (PH). Hypoxia‐inducible factor (HIF) is a well‐known modulator of hypoxia‐induced PH. The role and underlying mechanism of circRNAs in the regulation of HIF expression remains elusive. Methods and Results We profiled pulmonary artery transcriptomes using RNA sequencing and screened circRNAs associated with hypoxia treatment. The expression of a novel circRNA, circ_chr11_67292179–67294612 (circ‐myh8), was increased by hypoxia in a time‐dependent manner. We evaluated the effects of circ‐myh8 overexpression by adeno‐associated virus or inhibition by short hairpin RNA on proliferation and cell cycling in mice and pulmonary artery smooth muscle cells. Overexpression of circ‐myh8 promotes PH under normoxia, and disruption of circ‐myh8 by short hairpin RNA mitigates PH in chronic hypoxic mice. Biologically, circ‐myh8 induces the proliferation and cell‐cycle progression of pulmonary artery smooth muscle cells in vivo and in vitro. Mechanistically, RNA pull‐down and RNA immunoprecipitation assays were used to examine the interaction of circRNAs with the binding protein KAT7 (lysine acetyltransferase 7). The acetylation level of lysine 5 of histone H4 in the transcriptional initiation region of HIF1α was determined by chromatin immunoprecipitation assay followed by reverse transcription‐quantitative polymerase chain reaction. Circ‐myh8 acts as a modular scaffold to recruit histone acetyltransferase KAT7 to the promoters of HIF1α, which elicits acetylation of lysine 5 of histone H4 in their promoters. Conclusions Our findings not only reveal the pivotal roles of circ‐myh8 in governing histone modification in anti‐PH treatment but also advocate triggering the circ‐myh8/KAT7/HIF1α pathway to combat PH.

CircST6GAL1 knockdown alleviates pulmonary arterial hypertension by regulating miR‐509‐5p/multiple C2 and transmembrane domain containing 2 axis

“…22 Circ-myh8 overexpression accelerated PH in chronic hypoxic mice and induced PASMC proliferation in vitro and in vivo. 23 In our study, an elevated cir-cST6GAL1 expression in the serum of PAH patients and hypoxia-challenged HPASMCs was observed, indicating the potential implication of circST6GAL1 in PAH. Functionally, silencing of circST6GAL1 counteracted hypoxiaevoked proliferation, migration, and apoptosis arrest in HPASMCs, implying that circST6GAL1 may promote vascular remodeling by inducing VSMC synthetic switch to affect PAH.…”

Expression and regulation of HIF-1a in hypoxic pulmonary hypertension: Focus on pathological mechanism and Pharmacological Treatment

“…Recent research reveals that hypoxia elevates a novel circular RNA, circ-myh8, which acts as a modular scaffold, recruiting histone acetyltransferase KAT7 to the promoter of the HIF-1α gene and subsequently inducing PASMC proliferation and cell cycle progression. The study posits that circ-myh8 and its associated pathways may serve as pivotal targets for the diagnosis and treatment of HPH 37 .…”