Department of Pediatrics (Cardiology) (HT.V.H., N.S., S.L.P., S. Ranjbarvairi, D-Q.H., M.Z., G.F., D.B., S. Reddy), Stanford University, Palo Alto, CA.
Department of Bioengineering (I.S.L.), Stanford University, Palo Alto, CA.
Circulation. 2020 Oct 27;142(17):1667-1683. doi: 10.1161/CIRCULATIONAHA.120.045470. Epub 2020 Aug 18.
In patients with complex congenital heart disease, such as those with tetralogy of Fallot, the right ventricle (RV) is subject to pressure overload stress, leading to RV hypertrophy and eventually RV failure. The role of lipid peroxidation, a potent form of oxidative stress, in mediating RV hypertrophy and failure in congenital heart disease is unknown.
Lipid peroxidation and mitochondrial function and structure were assessed in right ventricle (RV) myocardium collected from patients with RV hypertrophy with normal RV systolic function (RV fractional area change, 47.3±3.8%) and in patients with RV failure showing decreased RV systolic function (RV fractional area change, 26.6±3.1%). The mechanism of the effect of lipid peroxidation, mediated by 4-hydroxynonenal ([4HNE] a byproduct of lipid peroxidation) on mitochondrial function and structure was assessed in HL1 murine cardiomyocytes and human induced pluripotent stem cell-derived cardiomyocytes.
RV failure was characterized by an increase in 4HNE adduction of metabolic and mitochondrial proteins (16 of 27 identified proteins), in particular electron transport chain proteins. Sarcomeric (myosin) and cytoskeletal proteins (desmin, tubulin) also underwent 4HNE adduction. RV failure showed lower oxidative phosphorylation (moderate RV hypertrophy, 287.6±19.75 versus RV failure, 137.8±11.57 pmol/[sec×mL]; =0.0004), and mitochondrial structural damage. Using a cell model, we show that 4HNE decreases cell number and oxidative phosphorylation (control, 388.1±23.54 versus 4HNE, 143.7±11.64 pmol/[sec×mL]; <0.0001). Carvedilol, a known antioxidant did not decrease 4HNE adduction of metabolic and mitochondrial proteins and did not improve oxidative phosphorylation.
Metabolic, mitochondrial, sarcomeric, and cytoskeletal proteins are susceptible to 4HNE-adduction in patients with RV failure. 4HNE decreases mitochondrial oxygen consumption by inhibiting electron transport chain complexes. Carvedilol did not improve the 4HNE-mediated decrease in oxygen consumption. Strategies to decrease lipid peroxidation could improve mitochondrial energy generation and cardiomyocyte survival and improve RV failure in patients with congenital heart disease.
在患有复杂先天性心脏病的患者中，如法洛四联症患者，右心室（RV）承受压力超负荷应激，导致 RV 肥厚，最终 RV 衰竭。脂质过氧化作用（一种强烈的氧化应激形式）在介导先天性心脏病中的 RV 肥厚和衰竭中的作用尚不清楚。
评估了来自 RV 肥厚但 RV 收缩功能正常的患者（RV 局部面积变化，47.3±3.8%）和 RV 收缩功能下降的 RV 衰竭患者（RV 局部面积变化，26.6±3.1%）的 RV 心肌中脂质过氧化、线粒体功能和结构。通过 HL1 鼠心肌细胞和人诱导多能干细胞衍生的心肌细胞评估脂质过氧化产物 4-羟壬烯醛 ([4HNE] 一种脂质过氧化的副产物) 对线粒体功能和结构的影响的机制。
RV 衰竭的特征是代谢和线粒体蛋白（27 个鉴定蛋白中的 16 个），特别是电子传递链蛋白的 4HNE 加合物增加。肌节（肌球蛋白）和细胞骨架蛋白（结蛋白、微管蛋白）也发生 4HNE 加合物。RV 衰竭表现出较低的氧化磷酸化（中度 RV 肥厚，287.6±19.75 与 RV 衰竭，137.8±11.57 pmol/[sec×mL]；=0.0004）和线粒体结构损伤。使用细胞模型，我们表明 4HNE 减少细胞数量和氧化磷酸化（对照，388.1±23.54 与 4HNE，143.7±11.64 pmol/[sec×mL]；<0.0001）。卡维地洛，一种已知的抗氧化剂，不会减少代谢和线粒体蛋白的 4HNE 加合物，也不会改善氧化磷酸化。
代谢、线粒体、肌节和细胞骨架蛋白易受 RV 衰竭患者 4HNE 加合物的影响。4HNE 通过抑制电子传递链复合物来降低线粒体氧消耗。卡维地洛不能改善 4HNE 介导的耗氧量降低。减少脂质过氧化的策略可以改善线粒体能量产生和心肌细胞存活，从而改善先天性心脏病患者的 RV 衰竭。
