Journal Article

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

Paolisso, Giuseppe, Capuano, Annalisa, Pesapane, Ada, Zia, Asad, Tortorella, Giovanni, Signoriello, Giuseppe, Barbieri, Michelangela, Scisciola, Lucia, Marfella, Ludovica Vittoria, Balzano, Nunzia, Fontanella, Rosaria Anna, Palazzo, Alberta Maria Maddalena, Sardu, Celestino, Basilicata, Manuela Giovanna, Arshad, Maryam, Ulfat, Zeeshan

2025

Overview

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. Graphical abstract

• Publisher: BioMed Central,Springer Nature B.V,BMC
• Subject: Adaptor Proteins, Signal Transducing - metabolism / Angiology / Animals / Anti-Inflammatory Agents - pharmacology / Apoptosis / Apoptosis - drug effects / Atherosclerosis / Biomarkers / Blood flow / Cardiology / Cardiomyocytes / Cardiovascular disease / Cardiovascular diseases / Cell Line / Cytokines / Diabetes / Eicosapentaenoic Acid - analogs & derivatives / Eicosapentaenoic Acid - pharmacology / Endothelium / Fatty acids / Gene expression / Glucose / Glucose - toxicity / Heart failure / Hemodynamics / Humans / Hyperglycaemia / Hyperglycemia / Inflammation / Inflammation Mediators - metabolism / Intracellular signalling / IPE / Mechano-transduction / Mechanotransduction / Mechanotransduction, Cellular - drug effects / Medicine / Medicine & Public Health / Meta-analysis / Molecular modelling / Mortality / Muscle contraction / Myocardial Contraction - drug effects / Myocytes, Cardiac - drug effects / Myocytes, Cardiac - metabolism / Myocytes, Cardiac - pathology / Omega-3 fatty acids / Oxidative metabolism / Oxidative stress / Oxidative Stress - drug effects / Shear stress / Signal transduction / Software / Stress, Mechanical / Transcription Factors - metabolism / YAP-Signaling Proteins / Yes-associated protein