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Excessive proliferation, migration, and antiapoptosis of pulmonary artery (PA) smooth muscle cells (PASMCs) underlies the development of pulmonary vascular remodeling. The innervation of the PA is predominantly sympathetic, and increased levels of circulating catecholamines have been detected in pulmonary arterial hypertension (PAH), suggesting that neurotransmitters released by sympathetic overactivation may play an essential role in PAH. However, the responsible mechanism remains unclear. Here, to investigate the effects of norepinephrine (NE) on PASMCs and the related mechanism, we used 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide, the proliferating cell nuclear antigen and the cell counting kit-8 assay to evaluate the proliferation of PASMCs, Boyden chamber migration, and wound-healing assays to assess migration and western blot analysis to investigate protein expression. We demonstrated that the phosphorylation level of the protein phosphatase 2A (PP2A) catalytic subunit (Y307) was higher in PAH patients and PAH models than in controls, both in vivo and in vitro. In addition, NE induced the proliferation and migration of PASMCs, which was attenuated by berberine (BBR), a Chinese herbal medicine, and/or PP2A overexpression. PP2A inhibition worsened NE-induced PAH and could not be reversed by BBR. Thus, PP2A is critical in driving PAH, and BBR may alleviate PAH via PP2A signaling pathways, thereby offering a potential therapeutic option for PAH.

This study aimed to determine the benefits and correlated mechanisms of pulmonary artery denervation (PADN) for heart failure (HF) pulmonary hypertension (PH). PH secondary to HF is associated with poor clinical outcomes because there is no proper therapy for it. PADN showed improved outcomes for patients with HF-PH. However, the underlying mechanisms remain unknown. Supracoronary aortic banding (SAB) was used to create HF-PH models. Sprague-Dawley rats were randomly assigned to control, SAB, sham, SAB with PADN, and SAB without PADN groups. Surgical (longitudinally damaging vessel nerves) and chemical (10% phenol applied to the surface of nerves) PADN was performed for animals in the SAB with PADN group. Morphological, echocardiographic, hemodynamic, and protein expression changes were measured four weeks thereafter. Adrenergic receptor (AR) expressions of pulmonary arteries from four HF-PH patients and four patients without PH were measured. Ten HF-PH patients who underwent PADN were followed-up for six months. SAB-induced HF-PH was achieved by 50% of animals. Surgical and chemical PADN was associated with significant improvements in pulmonary artery muscularization, hemodynamics, and right ventricular functions. In pulmonary arterial specimens from HF-PH patients, β2-AR and α1A/B-AR, as well as eNOS, were downregulated and α1D-AR was upregulated compared to those from patients without PH. PADN led to a mean increase of 84 m during the 6-min walk distance for HF-PH patients at six-month follow-up. HF-PH was characterized by downregulated β2-AR, α1A-AR, and α1B-AR and by upregulated α1D-AR. PADN is associated with significant improvements in hemodynamics and pulmonary artery remodeling.

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The clinical application of doxorubicin (Dox) is limited due to its cardiotoxicity, while the pathogenesis remains to be fully understood. Recent studies have suggested that microRNA (miRNA) plays an important role in Dox-induced cardiotoxicity. This work aims to investigate the effects of miR-125b in Dox-induced cardiotoxicity. Here, mice model combined with cell line analysis were used, and cell viability assay, detection of reactive oxygen species (ROS), malondialdehyde (MDA) activity, lactate dehydrogenase (LDH) activity, glutathione (GSH) level, glutathione peroxidase (GSH-Px) level, superoxide dismutase (SOD) activity, and histopathological changes were performed to characterize miR-125b effects; real-time quantitative polymerase chain reaction (PCR), luciferase reporter assay, RNA immunoprecipitation, and western blot analysis were subjected to reveal the underlying mechanisms. It was found that miR-125b level was upregulated in myocardial cell line H9C2 treated with Dox and miR-125b overexpression enhanced Dox-induced cytotoxicology of H9C2 cells, while miR-125b inhibition exhibited a protective effect by measuring ROS level and cell viability. In consistent, in vivo experiments with miR-125b agomir or antagomir obtained a consistent result through examining the activity of MDA, LDH, GSH, GSH-Px, SOD, and histopathological changes. Furthermore, we found that miR-125b could target STARD13 and thus suppressed the nucleus-cytoplasmic translocation of yesassociated protein (YAP). Additionally, this STARD13/YAP axis is necessary for miR-125b-mediated regulation on Dox-induced cytotoxicology of H9C2 cells. In conclusion, our study demonstrated that miR-125b could enhance Dox-induced cardiotoxicity through targeting the STARD13/YAP axis.

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