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Senolytics prevent caveolar CaV 3.2-RyR axis malfunction in old vascular smooth muscle.


ABSTRACT: Aging is a major risk factor for cardiovascular diseases. Our previous studies demonstrate that aging impairs the caveolar T-type CaV 3.2-RyR axis for extracellular Ca2+ influx to trigger Ca2+ sparks in vascular smooth muscle cells (VSMCs). We hypothesize that the administration of senolytics, which can selectively clear senescent cells, could preserve the caveolar CaV 3.2-RyR axis in aging VSMCs. In this study, 10-month-old mice were administered the senolytics cocktail consisting of dasatinib (5 mg/kg) and quercetin (50 mg/kg) or vehicle bi-weekly for 4 months. Using VSMCs from mouse mesenteric arteries, we found that Ca2+ sparks were diminished after caveolae disruption by methyl-β-cyclodextrin (10 mM) in cells from D + Q treated but not vehicle-treated 14-month-old mice. D + Q treatment promoted the expression of CaV 3.2 in 14-month-old mesenteric arteries. Structural analysis using electron tomography and immunofluorescence staining revealed the remodeling of caveolae and co-localization of CaV 3.2-Cav-1 in D + Q treatment aged mesenteric arteries. In keeping with theoretical observations, Cav 3.2 channel inhibition by Ni2+ (50 μM) suppressed Ca2+ in VSMCs from the D + Q group, with no effect observed in vehicle-treated arteries. Our study provides evidence that age-related caveolar CaV 3.2-RyR axis malfunction can be alleviated by pharmaceutical intervention targeting cellular senescence. Our findings support the potential of senolytics for ameliorating age-associated cardiovascular disease.

SUBMITTER: Lin J 

PROVIDER: S-EPMC10652315 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature

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Senolytics prevent caveolar Ca<sub>V</sub> 3.2-RyR axis malfunction in old vascular smooth muscle.

Lin Jie J   Guo Weiming W   Luo Qingtian Q   Zhang Qingping Q   Wan Teng T   Jiang Changyu C   Ye Yuanchun Y   Lin Haihuan H   Fan Gang G  

Aging cell 20231014 11


Aging is a major risk factor for cardiovascular diseases. Our previous studies demonstrate that aging impairs the caveolar T-type Ca<sub>V</sub> 3.2-RyR axis for extracellular Ca<sup>2+</sup> influx to trigger Ca<sup>2+</sup> sparks in vascular smooth muscle cells (VSMCs). We hypothesize that the administration of senolytics, which can selectively clear senescent cells, could preserve the caveolar Ca<sub>V</sub> 3.2-RyR axis in aging VSMCs. In this study, 10-month-old mice were administered the  ...[more]

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