Nifedipine-induced AMPK activation alleviates senescence by increasing autophagy and suppressing of Ca2+ levels in vascular smooth muscle cells. (September 2020)

• Record Type: Journal Article
• Authors: Kim, Seul Gi; Sung, Jin Young; Kim, Jae-Ryong; Choi, Hyoung Chul
• Is Part Of: Mechanisms of ageing and development. Volume 190(2020)
• Publication Date: 2020-09
• Subjects: AMPK AMP-activated protein kinase -- SMP30 senescence marker protein 30 -- 3-MA 3-methyladenine -- Baf A1 bafilomycin A1 -- mTOR mammalian target of rapamycin -- C.C compound C -- SA-β-gal senescence-associated β-galactosidase; Nifedipine -- Ca2+ -- Autophagy -- Senescence -- AMPK -- Vascular smooth muscle cell; Aging -- Periodicals; Developmental biology -- Periodicals; Aging -- Periodicals; Developmental Biology -- Periodicals; Vieillissement -- Périodiques; Biologie du développement -- Périodiques; Aging; Developmental biology; Periodicals; 612.67
• DOI: 10.1016/j.mad.2020.111314
• Languages: English
• ISSNs: 0047-6374

Abstract

Highlights: Calcium channel blocker, nifedipine suppresses senescence-related phenotypes. Oxidative stress-induced senescence was accompanied by Ca 2+ elevation and impairment of autophagic flux. Nifedipine alleviates VSMC senescence by regulating Ca 2+ influx and increasing autophagy. AMPK inhibition showed that the effect of nifedipine involved AMPK activation. Nifedipine-activated AMPK suppresses VSMC senescence by regulating Ca 2+ levels and autophagic flux. Abstract: Calcium (Ca 2+ ) homeostasis is disrupted during aging in several cell types and this disruption leads to autophagy impairment. The mechanisms regarding Ca 2+, senescence, and autophagy need to be elucidated. Therefore, we hypothesized that cellular senescence can be improved by regulating Ca 2+ level and autophagy activity. We identified that hydrogen peroxide (H2 O2 )-induced senescence was accompanied by Ca 2+ elevation, impairment of autophagic flux and increase of mammalian target of rapamycin (mTOR) phosphorylation in VSMCs. The treatment of nifedipine dose-dependently suppressed H2 O2 -induced senescence by reducing Ca 2+ entry, autophagy impairment and mTOR signaling, and this suppression was found to be related to senescence-associated β-galactosidase (SA-β-gal) activity and the expressions of senescence marker protein 30 (SMP30), p53, and p21. Furthermore, H2 O2 -induced autophagy impairment also accelerated senescence and accumulations of ubiquitinated proteins. AMPK inhibition or transfection with AMPK siRNA showed that the anti-senescence effect of nifedipine involved AMPK activation. These results suggest nifedipine-inducted AMPK activation suppresses VSMC senescence by regulating autophagic flux and Ca 2+ levels.