Department of Pediatrics.
Department of Biostatistics & Computational Biology, and.
JCI Insight. 2021 Mar 8;6(5):140785. doi: 10.1172/jci.insight.140785.
Preterm birth increases the risk for pulmonary hypertension and heart failure in adulthood. Oxygen therapy can damage the immature cardiopulmonary system and may be partially responsible for the cardiovascular disease in adults born preterm. We previously showed that exposing newborn mice to hyperoxia causes pulmonary hypertension by 1 year of age that is preceded by a poorly understood loss of pulmonary vein cardiomyocyte proliferation. We now show that hyperoxia also reduces cardiomyocyte proliferation and survival in the left atrium and causes diastolic heart failure by disrupting its filling of the left ventricle. Transcriptomic profiling showed that neonatal hyperoxia permanently suppressed fatty acid synthase (Fasn), stearoyl-CoA desaturase 1 (Scd1), and other fatty acid synthesis genes in the atria of mice, the HL-1 line of mouse atrial cardiomyocytes, and left atrial tissue explanted from human infants. Suppressing Fasn or Scd1 reduced HL-1 cell proliferation and increased cell death, while overexpressing these genes maintained their expansion in hyperoxia, suggesting that oxygen directly inhibits atrial cardiomyocyte proliferation and survival by repressing Fasn and Scd1. Pharmacologic interventions that restore Fasn, Scd1, and other fatty acid synthesis genes in atrial cardiomyocytes may, thus, provide a way of ameliorating the adverse effects of supplemental oxygen on preterm infants.
早产会增加成年后患肺动脉高压和心力衰竭的风险。氧气疗法会损害未成熟的心肺系统，这可能是导致早产儿成年后发生心血管疾病的部分原因。我们之前的研究表明，新生小鼠暴露于高氧环境中会导致 1 岁时出现肺动脉高压，此前还会出现未被充分理解的肺静脉心肌细胞增殖减少。我们现在发现，高氧还会减少左心房的心肌细胞增殖和存活，并通过干扰左心室的充盈而导致舒张性心力衰竭。转录组谱分析显示，新生期高氧会在小鼠的心房、HL-1 系鼠心房心肌细胞和从人类婴儿中分离出的左心房组织中永久性地下调脂肪酸合酶 (Fasn)、硬脂酰辅酶 A 去饱和酶 1 (Scd1) 和其他脂肪酸合成基因。抑制 Fasn 或 Scd1 会减少 HL-1 细胞的增殖并增加细胞死亡，而过表达这些基因则会在高氧环境中维持其扩张，这表明氧气通过抑制 Fasn 和 Scd1 直接抑制心房心肌细胞的增殖和存活。因此，恢复心房心肌细胞中 Fasn、Scd1 和其他脂肪酸合成基因的药物干预可能为改善早产儿补充氧气的不良影响提供了一种方法。
