Circ- calm4 Serves as an miR-337-3p Sponge to Regulate Myo10 (Myosin 10) and Promote Pulmonary Artery Smooth Muscle Proliferation

Pulmonary artery smooth muscle cell proliferation is the pathological basis of pulmonary vascular remodeling in hypoxic pulmonary hypertension. Recent studies suggest that circular RNA (circRNA) can regulate various biological processes, including cell proliferation. Therefore, it is possible that circRNA may have important roles in pulmonary artery smooth muscle cell proliferation in hypoxic pulmonary hypertension. In the present study, we aimed to identify functional circRNAs and clarify their roles and mechanisms in pulmonary artery smooth muscle cell proliferation in pulmonary hypertension. RNA sequencing identified 67 circRNAs that were differentially expressed in hypoxic lung tissues of mice. Screening by bioinformatics and quantitative polymerase chain reaction revealed significant elevation of a circRNA derived from alternative splicing of the calmodulin 4 gene (designated circ- calm4 ). Notably, this circRNA absorbed miR-337-3p . We further identified Myo10 (myosin 10) as a target protein of miR-337-3p . miR-337-3p bound to the 3′-untranslated region of Myo10 mRNA, thereby attenuating the translation of Myo10. Using loss-of-function and gain-of-function approaches, we found that circ- calm4 regulated cell proliferation by regulating the cell cycle. Additionally, we verified the functions of miR-337-3p and Myo10 in hypoxic pulmonary artery smooth muscle. Our results suggested that the circ- calm4 / miR-337-3p /Myo10 signal transduction axis modulated the proliferation of pulmonary artery smooth muscle cells at the molecular level, thus establishing potential targets for the early diagnosis and treatment of pulmonary hypertension.