Shi Pilong, Song Chao, Qi Hanping, Ren Jing, Ren Ping, Wu Jiabi, Xie Yawen, Zhang Meitian, Sun Hongli, Cao Yonggang
Department of Pharmacology, Harbin Medical University-Daqing, Daqing, Heilongjiang 163319, China.
Department of Pharmacology, Harbin Medical University-Daqing, Daqing, Heilongjiang 163319, China.
J Nutr Biochem. 2022 Jun;104:108972. doi: 10.1016/j.jnutbio.2022.108972. Epub 2022 Feb 26.
The molecular characteristics of ferroptosis in cardiac hypertrophy have been rarely studied. Especially, there have been no studies to investigate the regulatory mechanisms of docosahexaenoic acid (DHA) on ferroptosis in cardiac hypertrophy. This study was designed to determine the role of ferroptosis in microvascular injury, and investigate the contribution of DHA in suppressing ferroptosis and preventing pressure overload-mediated endothelial damage. Our results indicated that the expression of interferon regulating factor 3 (IRF3) was primarily inhibited by pressure overload and consequently caused endothelial ferroptosis. Nevertheless, administration of DHA increased IRF3 expression and provided a pro-survival advantage for the endothelial system in the context of pressure overload. Experimental studies clearly showed that inhibition of IRF3 down-regulated SLC7A11 expression, and the latter leaded to the increase in the activities of arachidonate 12-lipoxygenase, which obligated cardiac microvascular endothelial cells to undergo ferroptosis via augmenting lipid peroxides. Interestingly, DHA supplementation suppressed endothelial ferroptosis via up-regulation of IRF3. Taken together, our studies identified the IRF3-SLC7A11-arachidonate 12-lipoxygenase axis as a new pathway responsible for pressure overload-mediated microvascular damage via initiating endothelial ferroptosis. In contrast, DHA treatment up-regulated the expression of IRF3 and thus reduced cellular ferroptosis, conferring a protective advantage to the endothelial system in pressure overload. These findings revealed that targeting IRF3 might be a useful therapeutic strategy for cardioprotection in cardiac hypertrophy and heart failure.
心脏肥大中铁死亡的分子特征鲜有研究。尤其是，尚无研究探讨二十二碳六烯酸（DHA）对心脏肥大中铁死亡的调控机制。本研究旨在确定铁死亡在微血管损伤中的作用，并研究DHA在抑制铁死亡和预防压力超负荷介导的内皮损伤中的作用。我们的结果表明，压力超负荷主要抑制干扰素调节因子3（IRF3）的表达，从而导致内皮铁死亡。然而，给予DHA可增加IRF3表达，并在压力超负荷情况下为内皮系统提供生存优势。实验研究清楚地表明，抑制IRF3可下调溶质载体家族7成员11（SLC7A11）的表达，而后者导致花生四烯酸12-脂氧合酶活性增加，这促使心脏微血管内皮细胞通过增加脂质过氧化物而发生铁死亡。有趣的是，补充DHA可通过上调IRF3来抑制内皮铁死亡。综上所述，我们的研究确定了IRF3-SLC7A11-花生四烯酸12-脂氧合酶轴是一条通过引发内皮铁死亡导致压力超负荷介导的微血管损伤的新途径。相反，DHA处理上调了IRF3的表达，从而减少细胞铁死亡，在压力超负荷时为内皮系统提供保护优势。这些发现表明，靶向IRF3可能是心脏肥大和心力衰竭中一种有用的心脏保护治疗策略。
