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.
Twelve months of oral sildenafil treatment was well tolerated and appeared to improve exercise capacity, systemic arterial oxygen saturation and haemodynamic parameters in patients with Eisenmenger syndrome.
Objective: Circular RNAs are emerging as important regulators of pulmonary hypertension where pyroptosis plays a critical role. However, whether and how the circular RNAs regulate pyroptosis remained unexplored. Here, we show evidence for the involvement of a specific circular RNA known as circ-Calm4 in pulmonary hypertension and the underlying signaling pathway in pyroptosis. Approach and Results: Circ-Calm4 was upregulated in both mouse model of pulmonary hypertension in vivo and cultured smooth muscle cells in vitro. We performed immunoblotting, quantitative real-time PCR, LDH (lactate dehydrogenase) release assay, Annexin V-FITC/propidium iodide double staining, Hoechst 33342/propidium iodide fluorescence staining, and immunostaining to clarify the roles of circ-Calm4 in pulmonary arterial smooth muscle cell pyroptosis. Silencing the circ-Calm4 with its small-interfering RNA mitigated the upregulation of pyroptosis related phenotypes induced by hypoxia. Luciferase reporter assays confirmed that miR-124-3p suppressed the luciferase activity of the circ-Calm4 and RNA fluorescence in situ hybridization showed the colocalization of circ-Calm4 and miR-124-3p. The circ-Calm4 was found to act as a competitive endogenous RNA to regulate miR-124-3p. The pyroptosis-related alterations were all diminished with miR-124-3p in hypoxic pulmonary arterial smooth muscle cells. Inhibition of the gene targeted by miR-124-3p encoding the Pdcd6 (programmed cell death protein 6) abrogated pyroptosis-related phenotypes under hypoxia stimulation. Conclusions: Our findings show a new signaling pathway, the circ-Calm4/miR-124-3p/ Pdcd6 axis was demonstrated in regulation of hypoxia-induced pyroptosis, which may potentially be useful for the design of therapeutic strategies for protecting the cellular functionality against pyroptosis as well as pulmonary hypertension.
BackgroundAlthough several new drugs have been approved in recent years, pulmonary arterial hypertension (PAH) remains a rapidly progressive disease with a poor prognosis. Ambrisentan, a selective endothelin type A antagonist, has been approved for treatment of PAH. This open label study assessed the efficacy and safety of ambrisentan in Chinese subjects with PAH.MethodsEligible patients with PAH (World Health Organisation [WHO] functional class [FC] II orIII) were enrolled and received Ambrisentan (5 mg) once daily for a 12-week preliminary evaluation period, and a 12-week dose-adjustment period (dose titration to 10 mgallowed). Endpoints included: change from baseline in 6-Minute Walk Distance (6-MWD), N-Terminal Pro B-Type Natriuretic Peptide (NT-pro-BNP), WHO FC, Borg Dyspnoea Index (BDI), clinical worsening of PAH and incidences of adverse events (AE).ResultsOne hundred thirty-three subjects (85 % women, mean age: 36 years) with PAH (WHOFC II or III) were enrolled and received ambrisentan (5 mg) once daily for a 12-week preliminary evaluation period, and a 12-week dose-adjustment period. Mean (SD) duration of drug exposure was 161.7 (27.13) days. Ambrisentan (average daily dose of 6.27 mg) significantly improved exercise capacity (6MWD) from baseline (mean: 377.1 m [m]) at week 12 (+53.6 m, p < 0.001) (primary endpoint). Improvement in exercise capacity was noted as early as week 4, and was sustained up to week 24 (+ 64.4 m, p < 0.001). NT-pro-BNP plasma levels decreased significantly (p < 0.001) at week 12 (−861.4 ng/L) and week 24 (−806 ng/L) from baseline (mean: 1600.7 ng/L). The WHO FC showed improvements for 44 subjects at week 12 and 51 subjects at week 24. BDI scores decreased significantly at week 12 (−0.3, p < 0.001) and week 24 (−0.2, p = 0.003) from baseline (mean: 2.5). Four patients died during the study (sudden cardiac death [n = 2], cerebral haemorrhage [n = 1], cardiac failure [n = 1]). Drug related adverse events occurred in 34.3 % of subjects; peripheral oedema (11.2 %) and flushing (8.2 %) occurred most frequently.ConclusionAmbrisentan (5 and 10 mg, orally) significantly improved the exercise capacity in Chinese PAH subjects with a safety profile similar to that observed in global studies.Trial registrationNCT No. (ClinicalTrials.gov): NCT01808313; Registration date (first time): February 28, 2013.Electronic supplementary materialThe online version of this article (doi:10.1186/s12872-016-0361-9) contains supplementary material, which is available to authorized users.
Aims This study aimed to assess the clinical characteristics and long-term survival outcome in patients with Takayasu’s arteritis-associated pulmonary hypertension (TA-PH). Methods and results We conducted a nationally representative cohort study of TA-PH using data from the National Rare Diseases Registry System of China. Patients with pulmonary artery involvement who fulfilled the diagnostic criteria of Takayasu’s arteritis and pulmonary hypertension were included. The primary outcome was the time from diagnosis of TA-PH to the occurrence of all-cause death. Between January 2007 and January 2019, a total of 140 patients were included, with a mean age of 41.4 years at diagnosis, and a female predominance (81%). Patients with TA-PH had severely haemodynamic and functional impairments at diagnosis. Significant improvements have been found in N-terminal pro-B-type natriuretic peptide (NT-proBNP) and haemodynamic profiles in patients with TA-PH receiving drugs approved for pulmonary arterial hypertension. The overall 1-, 3-, and 5-year survival rates in TA-PH were 94.0%, 83.2%, and 77.2%, respectively. Predictors associated with an increased risk of all-cause death were syncope [adjusted hazard ratio (HR) 5.38 (95% confidence interval 1.77–16.34), P = 0.003], NT-proBNP level [adjusted HR 1.04 (1.03–1.06), P < 0.001], and mean right atrial pressure [adjusted HR 1.07 (1.01–1.13), P = 0.015]. Conclusion Patients with TA-PH were predominantly female and had severely compromised haemodynamics. More than 80% of patients in our cohort survived for at least 3 years. Medical treatment was based on investigators’ personal opinions, and no clear risk-to-benefit ratio can be derived from the presented data.
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