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Canagliflozin Delays Aortic Valve Calcification by Enhancing the AMPK/Nrf2/HO-1 Antioxidant Signaling Pathway in
Quangong Zhao1, Boyao Zhang1, Xiaoxian Wang2
1Department of Cardiovascular Surgery, Changhai Hospital, Naval Medical University, Shanghai, China.
Abstract:
Aortic valve calcification is a significant contributor to the development of aortic valve stenosis, a condition for which effective pharmacological treatments are currently limited. Sodium-glucose cotransporter 2 inhibitors, such as canagliflozin (CANA), have demonstrated promising cardioprotective effects, irrespective of diabetes status. This study aims to investigate the therapeutic effects and underlying mechanisms of CANA on aortic valve calcification. In an aortic valve wire injury mouse model, treatment with CANA significantly reduced aortic valve peak velocity, inhibited leaflet thickening, and decreased calcium deposition. Furthermore, CANA enhanced the expression of nuclear factor erythroid-2-related factor 2 (Nrf2) and heme oxygenase (HO-1) and reduced the levels of the oxidative stress marker 8-OHdG. In an in vitro osteogenic model of valvular interstitial cells (VICs), CANA treatment effectively reduced the expression of alkaline phosphatase (ALP) and runt-related transcription factor 2 and decreased the formation of calcium nodules. Additionally, CANA activated the Nrf2/HO-1 antioxidant signaling pathway in VICs under calcification induction conditions, while significantly reducing the accumulation of reactive oxygen species and mitochondrial superoxide. In an ex vivo model of human aortic valve calcification, CANA treatment led to a reduction in calcified nodule formation and ALP expression, along with the activation of the Nrf2/HO-1 signaling pathway and a decrease in 8-OHdG levels. The protective effects of CANA on aortic valve calcification were partially reversed by the Nrf2 inhibitor ML385 or small interfering RNA-mediated NRF2 knockdown, confirming the involvement of the Nrf2/HO-1 pathway. Importantly, CANA-induced Nrf2/HO-1 activation in VICs was mediated by the AMPK pathway. In summary, CANA effectively delayed aortic valve calcification by enhancing the AMPK/Nrf2/HO-1 antioxidant signaling pathway, suggesting that CANA may hold therapeutic potential for preventing or slowing the progression of aortic valve stenosis.
Insights
Canagliflozin (CANA) effectively delays aortic valve calcification by activating the AMPK/Nrf2/HO-1 antioxidant pathway. This suggests CANA may be a potential treatment for aortic valve stenosis.
Area of Science:
- Cardiovascular Research
- Pharmacology
- Biochemistry
Background:
- Aortic valve calcification contributes to aortic valve stenosis, with limited pharmacological treatments.
- Sodium-glucose cotransporter 2 inhibitors (SGLT2i), like canagliflozin (CANA), show cardioprotective effects.
- The therapeutic potential of CANA in aortic valve calcification requires further investigation.
Purpose of the Study:
- To investigate the therapeutic effects of CANA on aortic valve calcification.
- To elucidate the underlying mechanisms of CANA's action.
- To evaluate CANA's impact on oxidative stress and antioxidant pathways.
Main Methods:
- Aortic valve wire injury mouse model.
- In vitro osteogenic model using valvular interstitial cells (VICs).
- Ex vivo human aortic valve calcification model.
- Analysis of gene and protein expression, calcium deposition, and oxidative stress markers.
- Involvement of Nrf2/HO-1 and AMPK pathways investigated using inhibitors and knockdown.
Main Results:
- CANA treatment reduced aortic valve calcification markers (peak velocity, leaflet thickening, calcium deposition) in vivo.
- CANA inhibited osteogenic markers (ALP, RUNX2) and calcium nodule formation in vitro.
- CANA activated the Nrf2/HO-1 antioxidant pathway and reduced oxidative stress (8-OHdG, ROS, mitochondrial superoxide).
- CANA's protective effects were partially dependent on Nrf2 and mediated by the AMPK pathway.
Conclusions:
- CANA effectively delays aortic valve calcification through the AMPK/Nrf2/HO-1 antioxidant signaling pathway.
- CANA demonstrates therapeutic potential for preventing or slowing aortic valve stenosis progression.
- Targeting the AMPK/Nrf2/HO-1 pathway with CANA offers a promising strategy for valvular heart disease.
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