Cellular senescence impairs the reversibility of pulmonary arterial hypertension

Abstract

Pulmonary arterial hypertension (PAH) in congenital cardiac shunts can be reversed by hemodynamic unloading (HU) through shunt closure. However, this reversibility potential is lost beyond a certain point in time. The reason why PAH becomes irreversible is unknown. In this study, we used MCT+shunt-induced PAH in rats to identify a dichotomous reversibility response to HU, similar to the human situation. We compared vascular profiles of reversible and irreversible PAH using RNA sequencing. Cumulatively, we report that loss of reversibility is associated with a switch from a proliferative to a senescent vascular phenotype and confirmed markers of senescence in human PAH-CHD tissue. In vitro, we showed that human pulmonary endothelial cells of patients with PAH are more vulnerable to senescence than controls in response to shear stress and confirmed that the senolytic ABT263 induces apoptosis in senescent, but not in normal, endothelial cells. To support the concept that vascular cell senescence is causal to the irreversible nature of end-stage PAH, we targeted senescence using ABT263 and induced reversal of the hemodynamic and structural changes associated with severe PAH refractory to HU. The factors that drive the transition from a reversible to irreversible pulmonary vascular phenotype could also explain the irreversible nature of other PAH etiologies and provide new leads for pharmacological reversal of end-stage PAH.

Senolytics for Cancer Therapy: Is All that Glitters Really Gold?

“…Notably, the senolytic action of ABT-263 appears to depend on inhibition of BCL-X L and/or BCL-W, while BCL-2 inhibition is dispensable [84,86]. Similar to D+Q, ABT-263 was successful in eliminating senescent cell populations in several disease models including aging-associated bone loss [87], radiation-induced lung fibrosis [88], lung emphysema [89], uterine leiomyoma [90], tau-dependent neurodegenerative disease [91], radiation-induced neurodegeneration [92], myocardial infarction (including ischemia-reperfusion injury) [93,94], heart failure [95], pulmonary hypertension [96], insulin resistance [97], osteoarthritis [98,99], synthetic implant-mediated fibrosis [100], and Duchenne muscular dystrophy [101]. ABT-263 is currently a cornerstone in preclinical studies of senolysis and remains a promising drug for use against both liquid and solid tumors [102][103][104].…”

Endothelial Dysfunction in Pulmonary Hypertension: Cause or Consequence?

“…Interestingly, decreasing the pulmonary flow via banding prevented the development of plexiform lesions in a rat model of PAH, which suggests a causative role for increased force transmission in the initiation and development of PAH [ 76 , 77 ]. However, pulmonary artery banding in rats induced right ventricle dysfunction [ 78 ].…”

“…A recent study demonstrates that human pulmonary ECs of patients with PAH are more vulnerable to cellular senescence, a process that is associated with EC dysfunction. Interestingly, targeting senescence while using the senolytic drug ABT 263 reversed established PH in a MCT+shunt induced PAH rat model by specifically inhibiting senescent vascular cells [ 77 ]. However, more research should be performed on the safety and efficacy of senolytics in patients.…”

Endothelial cell senescence exacerbates pulmonary hypertension through Notch-mediated juxtacrine signaling

“…EC senescence has been considered to play a causative role in age-related metabolic (Shosha et al , 2018; Barinda et al , 2020) and cardiovascular disease (Minamino et al , 2002; Ahmad et al , 2015; Yamazaki et al , 2016; Shakeri et al , 2018; Song et al , 2020). Moreover, the potential role of cellular senescence has been explored in various non-age-related diseases such as type-1 diabetes (Thompson et al , 2019) and PAH associated with congenital heart disease (Van Der Feen et al , 2020). Senescence-associated secretory phenotype (SASP) has been highlighted as a non-cell-autonomous activity to bring detrimental effects to nearby cells (Tchkonia et al , 2013; Van Der Feen, Berger and Bartelds, 2019; Li and Lerman, 2020).…”

“…However, hemodynamic correction failed to maintain the lesion regression, and eventually irreversible phenotypes that resemble neointimal and plexiform lesions of PAH occur after a certain period. Cellular senescence has recently been revealed as the culprit of reversibility loss in PAH associated with hemodynamic abnormality (Hsu et al , 2016; van der Feen et al , 2017; Van Der Feen et al , 2020). Moreover, the potential link of vascular cell senescence in the pathophysiology of PAH has been recently explained (Van Der Feen, Berger and Bartelds, 2019).…”