Cardioprotective mechanism of ω-3 fatty acid icosapent ethyl (IPE) in cardiomyocytes: role in high glucose and shear stress-induced mechano-transduction dysregulation

Background: Omega-3 fatty acids (FAs) are long-chain fatty acids that have shown cardioprotective effects through lipid lowering, anti-inflammatory, and membrane-stabilizing properties. In this study we investigated the molecular mechanism underlying the cardioprotective effects of icosapent ethyl (IPE), an ethyl ester of omega-3 fatty (EPA), focusing on its role on mechano-transduction, a process linking cardiac contractility to intracellular signaling, that becomes dysregulated in hyperglycaemia or disturbed blood flow, both major contributors to cardiovascular diseases. Methods: We conducted in vivo meta-analyses to assess the beneficial effects of omega-3 fatty acids on cardiac contractility and inflammation in patients with cardiovascular and cardiometabolic diseases. We investigated the effects of IPE on mechano-transduction, assessing the activation of the YAP/TAZ signalling pathway, in cardiomyocyte cells AC16 exposed to normal (NG) or high glucose (HG) conditions. We defined the role of IPE against hyperglycaemia-induced inflammation, oxidative stress, metabolism, and apoptosis by evaluating key biomarkers by Western Blot and Real-time PCR. We evaluated IPE's impact on YAP/TAZ activation and on gene expression and protein levels of primary markers related to oxidative stress, inflammation, and metabolism in a dynamic flow model of AC16 cardiomyocytes, to mimic in vivo shear stress. Results: In vivo meta-analyses showed a significant increase of left ventricular ejection fraction (LVEF%) (mean: 0.5, 95% CI: 0.1-0.9) and a significant reduction of inflammatory markers (mean:  - 1.24, 95% CI: 2.05-0.44) in patients treated with omega-3. IPE treatment reduced the activation of YAP/TAZ pathway induced by HG exposure in AC16 cells. IPE partially reversed HG-induced changes in markers of inflammation, oxidative stress, metabolism and apoptosis (p < 0.05). Similarly, in a dynamic model of shear stress, IPE treatment mitigated the turbulent flow-mediated changes in YAP/TAZ pathway, inflammation, oxidative stress and metabolism. Conclusions: Our results demonstrate a cardioprotective role of IPE through modulation of hyperglycaemia-induced mechano-transduction dysregulation, inflammation, and oxidative stress. Additionally, our results on a shear stress model showing that IPE restores upstream regulators of YAP/TAZ and reduces disturbed flow-induced activation of pro-inflammatory pathways, suggest that IPE may exert a therapeutic effect on cardiovascular disorders associated with disturbed blood flow and hemodynamic stress.