Imbalanced ω-6/ω-3 polyunsaturated fatty acid metabolism promotes HFpEF progression via the ANGPTL4/LPL axis-mediated lipotoxicity
Z Zhang, J Wang, W Zhang, S He, Z Yuan, J Zhou, Y Wu, J SheAbstract
Background
Heart failure with preserved ejection fraction (HFpEF) is a growing global burden with limited therapeutic options. While lipid metabolic disorders are hallmarks of HFpEF, the specific contribution of imbalanced -6/-3 polyunsaturated fatty acids (PUFAs) to myocardial lipid handling remains poorly understood. This study aims to elucidate how -6/-3 dysregulation drives HFpEF progression and to evaluate the therapeutic potential of targeting the ANGPTL4/LPL signaling axis.
Methods
Plasma fatty acid profiles were analyzed in HFpEF patients and healthy controls using targeted lipidomics. An in vivo HFpEF mouse model was established using a high-fat diet (HFD) combined with L-NAME to assess AAV9-mediated cardiac ANGPTL4 overexpression or knockdown. In vitro, neonatal rat cardiomyocytes (NRCMs) and H9c2 cells were treated with various fatty acids (palmitic acid (PA), oleic acid (OA), arachidonic acid (AA), and eicosapentaenoic acid (EPA)) under Angptl4 knockdown or overexpression to evaluate cell viability, lipid accumulation, and oxidative stress.
Results
(1) Clinical Lipidomics: HFpEF patients exhibited distinct lipidomic signatures, characterized by a significantly elevated -6/-3 ratio compared to controls. Notably, reduced plasma EPA levels were inversely correlated with the severity of clinical HFpEF phenotypes. (2) In Vivo Mechanisms: In HFpEF mice, myocardial Angptl4 expression was significantly upregulated alongside Lpl downregulation, indicating a compensatory but insufficient response to lipid overload. Cardiac-specific overexpression of ANGPTL4 significantly attenuated diastolic dysfunction, myocardial lipid accumulation and lipotoxicity. Conversely, Angptl4 knockdown exacerbated these pathological phenotypes, confirming its cardioprotective role. (3) In Vitro & Therapeutic Validation: Among the tested PUFAs, EPA demonstrated the most potent capacity to induce Angptl4 expression. Mechanistically, Angptl4 knockdown abolished the protective effects of EPA against oxidative stress and lipid accumulation. While EPA supplementation ameliorated HFpEF progression, these beneficial effects were largely abrogated in Angptl4-knockdown mice, confirming that EPA-mediated protection is dependent on the ANGPTL4/LPL axis.
Conclusion
Our findings reveal that imbalanced -6/-3 metabolism promotes HFpEF pathogenesis through myocardial lipotoxicity. EPA mitigates this injury specifically by activating the ANGPTL4/LPL pathway. Targeting this metabolic axis represents a promising nutritional and pharmacological strategy for HFpEF management.