Potential role of cellular senescence in pulmonary arterial hypertension

Abstract

Pulmonary arterial hypertension (PAH) is a rare and chronic lung vasculature disease characterised by pulmonary vasculature remodelling, including abnormal proliferation of pulmonary artery smooth muscle cells (PASMCs) and dysfunctional endothelial cells (ECs). Remodelling of the pulmonary vasculature occurs from maturity to senescence, and it has become apparent that cellular senescence plays a central role in the pathogenesis of various degenerative vascular diseases and pulmonary pathologies.Cellular senescence represents a state of stable proliferative arrest accompanied by the senescence-associated secretory phenotype (SASP), which entails the copious secretion of proinflammatory signals in the tissue microenvironment. Evidence shows that in PAH patients, higher levels of cytokines, chemokines and inflammatory mediators can be detected and correlate with clinical outcome. Moreover, senescent cells accrue with age in epithelial, endothelial, fibroblastic and immunological compartments within human lungs, and evidence has shown that ECs and PASMCs in lungs from patients with chronic obstructive pulmonary disease were characterised by a higher number of senescent cells. However, there is little evidence uncovering the molecular pulmonary vasculature senescence in PAH. Herein, we review the cellular senescence in pulmonary vascular remodelling, and emphasise its importance in PAH.We further introduce some signalling pathways which might be involved in vasculature senescence and PAH, with the intent to discuss the possibility of the PAH therapy via targeting cellular senescence and reduce PAH progression and mortality.

ZNF281 drives hepatocyte senescence in alcoholic liver disease by reducing HK2‐stabilized PINK1/Parkin‐mediated mitophagy

“…SASP is a critical marker for cellular senescence, which promotes the production of proinflammatory cytokines. 21 Proinflammatory cytokines IL‐1β and IL‐6 were significantly increased in culture supernatant of ethanol‐treated hepatocytes, while ZNF281 silence reduced the release of IL‐1β and IL‐6 under ethanol stimulation (Figure 3C,D ). Senescent hepatocytes are also featured by lipometabolic disorder.…”

“…Flow cytometry showed that control hepatocytes were arrested at G0/G1 phase by ethanol incubation, while ZNF281‐knockdown hepatocytes were resistant to ethanol insult, released from G0/G1 phase, and entered S phase (Figure 3B). SASP is a critical marker for cellular senescence, which promotes the production of proinflammatory cytokines 21 . Proinflammatory cytokines IL‐1β and IL‐6 were significantly increased in culture supernatant of ethanol‐treated hepatocytes, while ZNF281 silence reduced the release of IL‐1β and IL‐6 under ethanol stimulation (Figure 3C,D).…”

Therapeutic targeting of mineralocorticoid receptors in pulmonary hypertension: Insights from basic research

“…Likewise, a lower degree of perivascular lung inflammation in response to hypoxia-sugen was observed in mice with SMC-specific deletion of MR compared to wild type ( 47 ). In addition, aldosterone may exert adverse effects on PASMCs by promoting cell senescence as aldosterone has been shown as one the strong pro-senescent factors in the pathogenesis of cardiovascular diseases ( 49 ), which also play a crucial role in the pathobiology of PH ( 50 ). However, the evidence directly linking aldosterone signaling with cellular senescence in the development of PH is still lacking and should focus of the future investigation.…”