Abstract
ObjectivesPulmonary hypertension (PH) is a life-threatening progressive disease with high mortality in the elderly. However, the pathogenesis of PH has not been fully understood and there is no effective therapy to reverse the disease process. This study aims to determine whether cellular senescence is involved in the development of PH.MethodsThe rat PH model was established by intraperitoneal injection of monocrotaline and evaluated by pulmonary arteriole wall thickness and right ventricular hypertrophy index. Human lung fibroblasts (HLFs) were treated with CoCl2 or hypoxia to induce cellular senescence in vitro. SA-β-gal staining and the changes of senescent markers were used to examine cellular senescence. The molecular mechanism of cellular senescence was further explored by detecting reactive oxygen species (ROS) levels and culturing cells with a conditioned medium.ResultsWe revealed the cellular senescence of pulmonary adventitial fibroblasts in vivo in the rat PH model. The expression of Bmi-1, an important regulator of senescence, was decreased in the lungs of PH rats and localized in adventitial fibroblasts. The in vitro experiments showed that p16 expression was increased while Bmi-1 expression was decreased after CoCl2 treatment in HLFs. Mechanistically, Bmi-1 could alleviate CoCl2-induced HLFs senescence by eliminating ROS which further promoted the proliferation of pulmonary artery smooth muscle cells by paracrine mode of action of HLFs.ConclusionBmi-1 alleviates the cellular senescence of pulmonary fibroblasts in PH, which expands the pathogenesis of PH and provides a theoretical basis for targeting senescent cells in the treatment of PH.
Highlights
Pulmonary hypertension (PH) is a life-threatening progressive disease with elevated pulmonary artery pressures caused by various conditions
Adventitial fibroblasts senescence is observed in MCT‐induced PH rat model To determine if cellular senescence was involved in PH lungs, we constructed an MCT-induced PH rat model
These results confirmed lung tissue senescence in the MCT-induced PH rat model and demonstrated that pulmonary adventitial fibroblasts are the main cell type involved in cellular senescence
Summary
Pulmonary hypertension (PH) is a life-threatening progressive disease with elevated pulmonary artery pressures caused by various conditions. Cellular senescence is a cell state triggered by a variety of stressors, such as genotoxic agents, nutritional deficiencies, hypoxia, mitochondrial dysfunction, and oncogene activation [6, 7]. It is characterized by a prolonged and generally irreversible cell-cycle arrest, apoptosis resistance, and abnormal expression of senescence-associated secretory phenotype (SASP) factors (IL-6, IL-8, IFN-γ, etc.) under various physiological processes and a wide spectrum of age-related disease conditions [8]. The increased activity of SA-β-gal and elevated expression of p16, p19, p21, and p53, as well as the SASP factors, are considered as the main markers of cellular senescence [7, 9,10,11]. Few studies have explored the effect of cellular senescence on PH, and the molecular mechanism underlying which is still unknown
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