Metformin ameliorates valve interstitial cell calcification by promoting autophagic flux.

Autor: Phadwal K; The Roslin Institute & R(D)SVS, University of Edinburgh, Easter Bush, Midlothian, EH25 9RG, UK. kanchan.phadwal@roslin.ed.ac.uk., Tan X; The Roslin Institute & R(D)SVS, University of Edinburgh, Easter Bush, Midlothian, EH25 9RG, UK.; Guangzhou Institute of Cardiovascular Diseases, Key Laboratory of Cardiovascular Diseases, School of Basic Medical Sciences, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, China., Koo E; The Roslin Institute & R(D)SVS, University of Edinburgh, Easter Bush, Midlothian, EH25 9RG, UK., Zhu D; Guangzhou Institute of Cardiovascular Diseases, Guangdong Key Laboratory of Vascular Diseases, State Key Laboratory of Respiratory Disease, The Second Affiliated Hospital, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China., MacRae VE; The Roslin Institute & R(D)SVS, University of Edinburgh, Easter Bush, Midlothian, EH25 9RG, UK.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2023 Dec 05; Vol. 13 (1), pp. 21435. Date of Electronic Publication: 2023 Dec 05.
DOI: 10.1038/s41598-023-47774-6
Abstrakt: Calcific aortic valve disease (CAVD) is the most common heart disease of the developed world. It has previously been established that metformin administration reduces arterial calcification via autophagy; however, whether metformin directly regulates CAVD has yet to be elucidated. In the present study we investigated whether metformin alleviates valvular calcification through the autophagy-mediated recycling of Runx2. Calcification was reduced in rat valve interstitial cells (RVICs) by metformin treatment (0.5-1.5 mM) (P < 0.01), with a marked decrease in Runx2 protein expression compared to control cells (P < 0.05). Additionally, upregulated expression of Atg3 and Atg7 (key proteins required for autophagosome formation), was observed following metformin treatment (1 mM). Blocking autophagic flux using Bafilomycin-A1 revealed colocalisation of Runx2 with LC3 puncta in metformin treated RVICs (P < 0.001). Comparable Runx2 accumulation was seen in LC3 positive autolysosomes present within cells that had been treated with both metformin and hydroxychloroquine in combination (P < 0.001). Mechanistic studies employing three-way co-immunoprecipitation with Runx2, p62 and LC3 suggested that Runx2 binds to LC3-II upon metformin treatment in VICs. Together these studies suggest that the utilisation of metformin may represent a novel strategy for the treatment of CAVD.
(© 2023. The Author(s).)
Databáze: MEDLINE
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