Senolytic Elimination Of Stress-Induced Premature Senescent Cells Alleviates The Formation Of Abdominal Aortic Aneurysms

BackgroundAbdominal aortic aneurysm(AAA)is one of the major causes of mortality worldwide.The only beneficial treatment for AAA is surgical repair for patients with symptoms or>55 mm in maximum diameter,however,over 95%of AAAs identified were<55 mm in diameter and lacked effective treatment.Unfortunately,the data from clinical trials showed that intervention in risk factors for AAA achieved only moderate or even negative effects on slowing AAA progression.The development of a noninvasive strategy to block the pathogenesis of AAA is awaited for limiting AAA development.Chronic exposure to risk factors for vascular diseases,such as hypertension and nicotine,promotes premature senescence in vascular cells by generating stress-dependent damage.An accumulating body of evidence has indicated that SIPS might be essential for mediating the pathogenesis of AAA.First,SIPS is closely associated with the inflammatory response in injured tissues.Previous studies confirmed that stress-induced premature senescent cells could secrete a cocktail of proinflammatory cytokines and chemokines,recruiting a large number of inflammatory cells into the vascular wall.In addition,SIPS could lead to excessive production of reactive oxygen species(ROS),thereby increasing oxidative stress-related damage in the aorta.Furthermore,stress-induced premature senescent cells induce the degradation of the extracellular matrix(ECM),by the secretion of matrix proteases,which contributes to destruction of the aortic middle layer and the subsequent dilation of the aorta.The integrative effect of SIPS on inflammation,oxidative stress,and ECM degradation,suggested that SIPS might mediate the pathogenesis of AAA.Senolytics therapy is a novel and effective pharmacological method to selectively eliminate senescent cells by targeting abnormally activated antiapoptotic pathways.Previous studies revealed that senolytics could release premature senescent cells burden and improve functional recovery after acute injury of several tissues in young mice and aged mouse models.We thus hypothesized that the application of senolytic drugs might alleviate AAA development by inhibiting SIPS.In the current study,we detected the existence of SIPS in human and mouse AAA samples and explored the effect of inhibition of SIPS by senolytics on AAA progression in two AAA models.Moreover,we investigated the underlying mechanism by which SIPS affects AAA pathology.Methods and ResultsValidation of SIPS and function experimentsResults:(1)SIPS exists in AAA samples from patients and AAA sections from Ang II-induced AAA models and elastase-induced AAA models.(2)ABT263 selectively eliminated premature senescent VSMCs in established SIPS model in vitro.(3)ABT263 reduced AAA incidence and related pathological changes by inhibiting SIPS.(4)BPTES restrained AAA development and related pathological changes by eliminating SIPS cells.Mechanism experiments(1)RNA sequencing results demonstrated that SIPS promoted the transformation of vascular smooth muscle cells(VSMCs),accelerating AAA formation.ABT263 reversed the adverse changes in VSMC phenotypic conversion in two AAA models.(2)Co-culture experiment revealed that SIPS facilitated the phenotypic switching of VSMCs via SASP.Single-cell RNA sequencing analysis and rescue experiment showed that FGF9 functions as the key SASP factor to regulate VSMC phenotypic switch.(3)Rescue experiment showed that FGF9 activated PDGFRβ/ERKl/2 in surrounding normal VSMCs and eventually resulting in the phenotypic switch.ConclusionStress-induced premature senescent cells promoted surrounding VSMC phenotypic switching by activating FGF9/PDGFRβ/ERK1/2 signaling and eventually induced AAA formation.Senolytics targeting SIPS might be a powerful approach for treating AAA.