What is the clinical evidence from this study?

Study design: Other. Population: Calcific aortic valve disease (in vitro model). Intervention: Metformin vs. Control cells (untreated/vehicle). Primary outcome: Calcification (calcium deposition) (p=<0.01).

December 5, 2023Open Access

Metformin ameliorates valve interstitial cell calcification by promoting autophagic flux

Q: What are the key findings of this study?

Metformin significantly reduced calcification in rat valve interstitial cells (P < 0.01) by promoting autophagic flux and the degradation of Runx2.

Key Result

Metformin significantly reduced calcification in rat valve interstitial cells (P < 0.01) by promoting autophagic flux and the degradation of Runx2.

Structured PICO

Does metformin reduce calcification in rat valve interstitial cells?

Population

In vitro study using rat valve interstitial cells (RVICs) cultured under calcifying conditions to investigate the effects of metformin.

Intervention

Metformin (0.5-1.5 mM) added at day 0

Comparator

Control cells receiving matching volumes of diluent (0.3% DMSO or water) in calcifying medium

Outcome

Valve interstitial cell calcification (calcium deposition quantified by HCl leaching and alizarin red staining) and Runx2 protein expression at 72 hourssurrogate

Metformin reduces calcification in rat valve interstitial cells by promoting autophagic degradation of the osteogenic transcription factor Runx2, suggesting a potential novel therapeutic strategy for calcific aortic valve disease.

Main Result

p-value: p=<0.01

Limitations

In vitro study using a rat cell line, requiring further validation in human cells or in vivo models.
The specific role of p62 in sequestering Runx2 within autophagosomes requires further investigation.
Runx2 lacks the traditional LIR motif for binding to LC3-II, so the exact binding mechanism needs further study.

Abstract

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.

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Cite This Study

Phadwal et al. (Tue,) conducted a other in Calcific aortic valve disease (in vitro model). Metformin vs. Control cells (untreated/vehicle) was evaluated on Calcification (calcium deposition) (p=<0.01). Metformin significantly reduced calcification in rat valve interstitial cells (P < 0.01) by promoting autophagic flux and the degradation of Runx2.

synapsesocial.com/papers/6a208d06430c4172f2301f74 https://doi.org/https://doi.org/10.1038/s41598-023-47774-6

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