Trans-Ferulic Acid, A Functional Phenolic Compound from Plants, Exerts Cellular Level Cardioprotection in Ischaemic H9c2 Cells by Modulating NRF2 and HIF1α Pathways

Background: Ischaemic heart disease (IHD) is currently managed by drugs and minimally invasive procedures. However, the necessity for safe, eco-friendly herbal-based medications is consistently advocated to prevent the side effects. Medicinal plants, rich in cardioprotective phytochemicals, offer promising potential for developing safer therapeutics to mitigate IHD progression while reducing treatment-related risks. Objectives: Trans-ferulic acid (TFA), a phenolic secondary metabolite recognised for its various pharmaceutical applications, has been selected for in vitro assessment of its toxicity and cardioprotective efficacy. Materials and Methods: H9c2 cells were exposed to ischaemic conditions and treated with varying concentrations of TFA (3.1–50 µg/mL). Cytotoxicity and cardioprotective effects were assessed using MTT and lactate dehydrogenase (LDH) assays. Collagen degradation was evaluated by Sirius Red staining, while quantitative real-time polymerase chain reaction (qRT-PCR) was used to analyse the expression of nuclear factor erythroid 2-related factor 2 (NRF2) and HIF1α genes involved in oxidative stress response and hypoxia regulation. Results: 50 µg/mL TFA showed significantly (p < .001) less toxicity and exhibited 86% viability in ischaemic H9c2 cells; the protective levels were significantly (p < .001) higher (36%) when compared to the untreated group. Decreased LDH activity in the treated group demonstrated the cardioprotective efficacy of TFA, with a value of 239 U/mL compared to the untreated cells (356 U/mL). TFA inhibited the collagen degradation induced by ischaemia, hence preventing the organisation of cardiac muscle tissue, as evidenced by Sirius Red staining. TFA treatment upregulates the NRF2 and suppresses the expression of HIF1α by means of mitigating cellular damage caused by oxidative stress and inflammation, which has a significant impact on the occurrence of IHD. Conclusion: These findings suggest TFA as a promising phytochemical candidate for developing novel therapeutic strategies against IHD.