Abstract Background Pulmonary arterial hypertension (PAH) is a process of lung vascular remodeling which can lead to right heart dysfunction and significant morbidity. Previous studies have demonstrated the important role of mitochondrial dynamics in the progress of PAH. However, the mechanisms link between mitochondrial dynamics and PAH remains elusive. Our previous RNA-seq analyses showed an increased expression of cAMP response elements (CRE) in lungs tissues from monocrotaline (MCT)-induced PAH rats. Furthermore, cAMP response element binding protein (CREB), a transcription factors which could bind to the promoter of mitochondrial fission 1 protein (Fis1) and regulate its transcription, could promote the proliferation of cells. Here, we identified an essential role and mechanism of CREB in protecting against the progress of PAH. Purpose To identified an essential role and mechanisms of CREB in protecting against PAH. Methods In vivo, rats were divided into three groups, control group (Ctrl,received and identical volume of normal saline on days 0 and 7), MCT-induced PAH group (PAH, received twice injections of 20 mg/kg MCT on days 0 and 7), and 666-15 therapy group (PAH+666-15,received 6mg/kg 666-15 every two days and twice injections of 20 mg/kg MCT on days 0 and 7). In vitro, PASMCs were pretreated with CREB-inhibitor 666-15 after 24 hrs starvation. Characteristic changes of pulmonary arterial variables and right ventricle features were evaluated 4 weeks after the first-time injection. The expression level of mRNA and proteins levels of CREB and mitochondrial related proteins were measured. Results Compared to control groups, the mean pulmonary arterial pressure (mPAP), right ventricular hypertrophy index (RVHI), percentage of total wall thickness to external diameters of pulmonary arterioles diameter (WT%) and the percentage of wall area to the total area of vessels (WA%), right ventricular end diastolic diameter (RVEED) and right ventricular end systolic diameter (RVESD) were higher in those with PAH, which could be rescued after 666-15 therapy(Fig.1, Fig.2). The tricuspid annular plane systolic excursion (TAPSE), adjusted pulmonary artery acceleration time (PAAT/HR), left ventricular fraction shortening rate (LVFS%), right ventricular fraction shortening rate (RVFS%) were lower in PAH-rats when compared to control groups, which also could be reversed after 666-15 therapy (Table 1.). In addition, compared to control groups, the expression of Drp1, Fis1 mRNA as well as Drp1, Fis1, PCNA proteins were increase both in lung and PASMCs in PAH-rats, while the expression of Mfn2 protein was decrease. After 666-15 injection or treatment of 666-15 in vitro, the expression of Fis1 mRNA and protein was reduce compare to PAH-rats, but the expression of Drp1 and Mfn2 mRNA as well as proteins have no changed. Conclusion 666-15, a CREB inhibitor, could protect against MCT-induced PAH, which may be via preventing mitochondrial fission.Effects of CREB-inhibitor in rats. Effects of CREB-inhibitor in PASMCs.
Gong et al. (Sat,) studied this question.