Frataxin deficiency promotes endothelial senescence in pulmonary hypertension

Senescence Alterations in Pulmonary Hypertension

“…A recent study showed that counteracting cell senescence by navitoclax alters pulmonary hemodynamics in healthy animals and aggravates experimental PH [ 162 ]. This result contradicts those reported by Cullet et al [ 119 ], which concluded that navitoclax reduces vascular remodeling and improves hemodynamics in in vivo animal models of PH. This controversy suggests that the role of senescent cells in the development of PH has not yet been elucidated and further study is needed.…”

“…There is no more data from clinical trials of senolytics therapies, but pre-clinical trials have been carried out in PH animal models. Navitoclax administration reduced SASP-dependent interstitial immune cell elevation in the vasculature, vessel remodeling, and consequent hemodynamic manifestation of PH in hypoxic mice and hypoxic IL-6 transgenic mice [ 119 ]. Hsp90 inhibitors have been identified as a novel class of senolytics because Hsp90 prevents apoptosis of senescent cells; therefore, its inhibition induces apoptosis [ 120 ].…”

“…It could lead to misinterpretation of the data because the inhibition of some of them may have promoted improvements in the pathophysiology of PH and may not be due to the senolytic effects of the drug. For instance, navitoclax (ABT263), a Bcl2 inhibitor, has been used as a senolytic drug and has been shown to reduce SASP elevation, vessel remodeling, and consequent hemodynamic manifestation in hypoxic mice and hypoxic IL-6 transgenic mice [ 119 ]. However, maybe part of the data are related to antiproliferative properties.…”

Endothelial Senescence: A New Age in Pulmonary Hypertension

“…Moving downstream, a comprehensive pulmonary endothelial SASP profile and its corresponding paracrine and endocrine effects in PH also are incompletely defined. Endothelial senescence disrupts homeostatic intercellular signaling as evidenced by SASP-dependent pulmonary artery smooth muscle changes 79 and wholevessel remodeling 86 46 As such, the SASP profile for senescent pulmonary endothelial cells in PH is still incompletely characterized across these broad contexts. More data are also required to determine how such endothelial senescent signaling specifically controls immune cell recruitment, potentially dependent upon chemokine and cytokine-driven recruitment of blood-borne monocytes and neutrophils to the vasculature in PH.…”

“…Senolytics target pro-survival pathways to induce senescent cell removal ABT-263 (Navitoclax), ABT-737 BCL-2 inhibitors trigger mitochondria-mediated apoptosis ABT-263 prevents disease in IL-6 transgenic and wild type mice exposed to chronic hypoxia, modeling group 1 and 3 PH, respectively. 86 ABT-263 reverses disease in MCT-treated rats refractory to hemodynamic unloading, modeling end-stage PAH-CHD. 79 Dasatanib+ Nonspecific tyrosine kinase inhibitor Treatment with dasatanib, and to a lesser extent other tyrosine kinase inhibitors, resulted in PAH development.…”