Long-term Dietary n3 Fatty Acid Prevents Aging-related Cardiac Diastolic and Vascular Dysfunction

Abstract
Aims: The prevalence of left ventricular (LV) diastolic and vascular dysfunction increases with age, eventually leading to heart failure with preserved ejection fraction (HFpEF). A preventive strategy is an unmet medical need. We and others reported previously on the beneficial effects of omega-3 fatty acid alpha linolenic acid (ALA) on cardiovascular disorders in animal models and translational studies. We now investigate whether long-term dietary ALA could prevent LV diastolic dysfunction and vascular aging in a murine model.
Methods and Results: Wild-type C57BL/6J mice were fed a chow or ALA diet for 12 months, starting at 6 months of age. Here, we show that aged (~18 months) mice recapitulate major hallmarks of HFpEF, including LV diastolic dysfunction with preserved ejection fraction, impaired vascular function, cardiac fibrosis, arterial stiffening and inflammation, as well as elevated B-type natriuretic peptide (BNP). Long-term ALA supplementation upregulated the mitochondrial tricarboxylic acid enzyme Idh2 and the antioxidant enzymes SOD1 and Gpx1. It also counteracted inflammation and ECM remodeling by regulating NF-κB and in turn significantly reducing fibrosis biomarkers MMP-2/TGF-β in both cardiac and vascular tissues obtained from aged mice. These mechanisms emphasize the beneficial preventive effects of ALA on LV diastolic dysfunction, impaired vasorelaxation, cardiac fibrosis, inflammation and arterial stiffening in aged mice, considered as hallmarks of HFpEF.
Conclusions: We provide evidence and mechanistic insight on how long-term ALA supplementation is a successful strategy to prevent the development of age-related diastolic and vascular dysfunction.

摘要：
研究目的：左心室（LV）舒张和血管功能障碍的患病率随年龄增长而增加，最终导致保留射血分数的心力衰竭（HFpEF）。预防策略是一项未满足的医疗需求。我们及其他研究者先前报道了ω-3脂肪酸α-亚麻酸（ALA）在动物模型和转化研究中对心血管疾病的益处。本研究旨在探究长期摄入ALA是否能够预防小鼠模型中LV舒张功能障碍和血管老化。
研究方法与结果：对野生型C57BL/6J小鼠进行为期12个月的饲料喂养，其中一组以ALA饮食开始于6个月大。在此，我们展示了老年（约18个月）小鼠复制了HFpEF的主要特征，包括保留射血分数的LV舒张功能障碍、受损的血管功能、心脏纤维化、动脉僵化与炎症，以及B型利钠肽（BNP）水平升高。长期ALA补充上调了线粒体三羧酸酶Idh2和抗氧化酶SOD1及Gpx1。此外，通过调节NF-κB减轻炎症和细胞外基质（ECM）重塑，显著降低了来自老年小鼠的心脏和血管组织中纤维化生物标志物MMP-2/TGF-β。这些机制强调了ALA在预防老年小鼠LV舒张功能障碍、受损血管舒张、心脏纤维化、炎症和动脉僵化方面的有益预防作用，这些均被视为HFpEF的标志。
结论：本研究提供了证据和机制洞察，证明了长期ALA补充是一种成功的预防与年龄相关的舒张和血管功能障碍的策略。