Methylophiopogonanone A mitigates myocardial ischemia-reperfusion injury: involvement of VEGFR2-associated PI3K/Akt/GSK-3β signaling and suppression of mPTP opening.
MOA shows potential for reducing myocardial injury in rats, but human studies are needed to confirm its clinical relevance.
Where it sits
this study against the rest of the mots-c corpusSummary and findings
The study investigated the cardioprotective effects of Methylophiopogonanone A (MOA) in a rat model of myocardial ischemia-reperfusion injury (MIRI) and in primary cardiomyocytes. MOA was found to reduce infarct size and improve cardiac function, potentially through VEGFR2-associated PI3K/Akt signaling and suppression of mitochondrial permeability transition pore opening. The effects were partially attenuated by inhibitors and siRNA targeting VEGFR2 and PI3K, suggesting involvement of these pathways.
Abstract
<h4>Ethnopharmacological relevance</h4>Ophiopogonis Radix (Mai-Dong) has been widely used in traditional Chinese medicine for the treatment of cardiovascular diseases, particularly those associated with ischemia and impaired cardiac function. Methylophiopogonanone A (MOA), a bioactive homoisoflavonoid isolated from Ophiopogonis Radix, has demonstrated antioxidant and anti-inflammatory activities; however, its role and molecular mechanisms in myocardial ischemia-reperfusion injury (MIRI) remain unclear.<h4>Aim of the study</h4>This study aimed to investigate the cardioprotective effects of MOA in MIRI and to determine whether VEGFR2-associated PI3K/Akt signaling, inhibitory phosphorylation of GSK-3β, and preservation of mitochondrial function contribute to these effects.<h4>Materials and methods</h4>MOA-VEGFR2 target engagement and stabilization were assessed using computational prediction and biochemical target-stability assays. The cardioprotective effects of MOA were evaluated in a rat myocardial ischemia-reperfusion model and in primary cardiomyocytes subjected to oxygen-glucose deprivation/reoxygenation (OGD/R), with emphasis on cardiac function, infarct size, mitochondrial injury, mitochondrial permeability transition pore (mPTP) opening, and VEGFR2/PI3K/Akt/GSK-3β signaling. The involvement of VEGFR2 and PI3K signaling was further examined using VEGFR2 siRNA, SU5416, and LY294002.<h4>Results</h4>Integrative target screening prioritized VEGFR2/KDR as a functionally relevant candidate target of MOA in MIRI. Molecular docking and molecular dynamics simulations provided structural predictions; DARTS, CETSA, and ITDRF-CETSA supported VEGFR2 target engagement by MOA, whereas CHX-chase analysis showed a prolonged VEGFR2 protein half-life. In vivo, MOA reduced infarct size, improved cardiac function, lowered serum CK-MB, LDH, and cTnI levels, increased myocardial ATP content and SOD activity, enhanced phosphorylation of VEGFR2, PI3K, Akt, and GSK-3β, suppressed mPTP opening, and preserved mitochondrial ultrastructure. In vitro, MOA improved the viability of OGD/R-treated cardiomyocytes, decreased apoptosis and ROS accumulation, restored ΔΨm and ATP production, and inhibited mPTP opening. These protective effects were partially attenuated by VEGFR2 silencing, SU5416, or LY294002, supporting roles for VEGFR2-associated PI3K/Akt signaling and inhibitory phosphorylation of GSK-3β in MOA-mediated cardioprotection.<h4>Conclusion</h4>MOA attenuates acute MIRI and preserves mitochondrial function. The findings support a model in which MOA-associated VEGFR2 target engagement and increased VEGFR2 protein stability are accompanied by enhanced PI3K/Akt signaling and inhibitory phosphorylation of GSK-3β. However, direct physical binding to VEGFR2 and classical VEGFR2 agonism were not established.
Background
Myocardial ischemia-reperfusion injury (MIRI) is a critical condition associated with cardiovascular diseases, often leading to impaired cardiac function. Traditional Chinese medicine has utilized Ophiopogonis Radix for cardiovascular ailments, and Methylophiopogonanone A (MOA), a compound derived from this plant, has shown potential antioxidant and anti-inflammatory properties. This study explores MOA's potential cardioprotective effects and the underlying molecular mechanisms in MIRI.
Methods
The study employed a rat model of myocardial ischemia-reperfusion injury and primary cardiomyocytes subjected to oxygen-glucose deprivation/reoxygenation. MOA's effects on cardiac function, infarct size, and mitochondrial parameters were assessed. Computational predictions and biochemical assays evaluated MOA's interaction with VEGFR2, while VEGFR2 and PI3K signaling pathways were further examined using specific inhibitors and siRNA.
Results
MOA significantly reduced infarct size and improved cardiac function in the rat model. It lowered serum markers of cardiac injury, increased myocardial ATP and SOD activity, and enhanced phosphorylation of VEGFR2, PI3K, Akt, and GSK-3β. MOA also suppressed mPTP opening and preserved mitochondrial ultrastructure. In vitro, MOA improved cardiomyocyte viability, decreased apoptosis, and restored mitochondrial function. The protective effects were partially mitigated by VEGFR2 and PI3K pathway inhibitors.
Interpretation
The study suggests that MOA exerts cardioprotective effects in MIRI through VEGFR2-associated PI3K/Akt signaling and mitochondrial preservation. While the findings are promising, the reliance on a rat model and the lack of direct evidence for VEGFR2 agonism limit the clinical applicability. Further research is needed to confirm these effects in humans and elucidate the precise mechanisms of action.
Key findings
- MOA reduced infarct size in a rat model of MIRI.
- Improved cardiac function and lowered serum CK-MB, LDH, and cTnI levels.
- Increased myocardial ATP content and SOD activity.
- Enhanced phosphorylation of VEGFR2, PI3K, Akt, and GSK-3β.
- Suppressed mPTP opening and preserved mitochondrial ultrastructure.
Limitations
- Rat model, no human data
- Mechanism of VEGFR2 interaction not fully established
- Partial attenuation of effects by pathway inhibitors