From the Cardiovascular Translational Science Institute (V.H.L., L.Z., A.H., A.F., B.A.T., W.K., P.F.K., J.S.J., I.M.R., G.D.L.) and Department of Pediatrics (V.H.L., L.Z., A.H., A.F., B.A.T., W.K., P.F.K., J.S.J., I.M.R., G.D.L.), University of Alberta, Edmonton, Canada; and Department of Medical Pharmacology, Ankara University, Ankara, Turkey (A.O.-B.).
Circ Res. 2015 Jun 19;117(1):41-51. doi: 10.1161/CIRCRESAHA.117.306585. Epub 2015 May 14.
Post-ischemic contractile dysfunction is a contributor to morbidity and mortality after the surgical correction of congenital heart defects in neonatal patients. Pre-existing hypertrophy in the newborn heart can exacerbate these ischemic injuries, which may partly be due to a decreased energy supply to the heart resulting from low fatty acid β-oxidation rates.
We determined whether stimulating fatty acid β-oxidation with GW7647, a peroxisome proliferator-activated receptor-α (PPARα) activator, would improve cardiac energy production and post-ischemic functional recovery in neonatal rabbit hearts subjected to volume overload-induced cardiac hypertrophy.
Volume-overload cardiac hypertrophy was produced in 7-day-old rabbits via an aorto-caval shunt, after which, the rabbits were treated with or without GW7647 (3 mg/kg per day) for 14 days. Biventricular working hearts were subjected to 35 minutes of aerobic perfusion, 25 minutes of global no-flow ischemia, and 30 minutes of aerobic reperfusion. GW7647 treatment did not prevent the development of cardiac hypertrophy, but did prevent the decline in left ventricular ejection fraction in vivo. GW7647 treatment increased cardiac fatty acid β-oxidation rates before and after ischemia, which resulted in a significant increase in overall ATP production and an improved in vitro post-ischemic functional recovery. A decrease in post-ischemic proton production and endoplasmic reticulum stress, as well as an activation of sarcoplasmic reticulum calcium ATPase isoform 2 and citrate synthase, was evident in GW7647-treated hearts.
Stimulating fatty acid β-oxidation in neonatal hearts may present a novel cardioprotective intervention to limit post-ischemic contractile dysfunction.
缺血后收缩功能障碍是新生儿患者先天性心脏缺陷手术矫正后发病率和死亡率升高的原因之一。新生儿心脏的预先存在的肥厚可以使这些缺血损伤恶化，这可能部分是由于脂肪酸β-氧化率低导致心脏的能量供应减少。
我们确定使用过氧化物酶体增殖物激活受体-α（PPARα）激活剂 GW7647 刺激脂肪酸β-氧化是否会改善因容积超负荷引起的心脏肥厚的新生兔心脏的心脏能量产生和缺血后功能恢复。
通过腹主动脉-腔静脉分流术在 7 天大的兔子中产生容量超负荷性心脏肥厚，之后，兔子用或不用 GW7647（每天 3mg/kg）治疗 14 天。双心室工作心脏接受 35 分钟的有氧灌注、25 分钟的全流量缺血和 30 分钟的有氧再灌注。GW7647 治疗不能预防心脏肥厚的发展，但可以防止体内左心室射血分数的下降。GW7647 治疗在缺血前后增加了心脏脂肪酸β-氧化率，导致整体 ATP 产生显著增加，并改善了体外缺血后功能恢复。GW7647 处理的心脏中明显减少了缺血后的质子产生和内质网应激，并且肌浆网钙 ATP 酶同工型 2 和柠檬酸合酶的活性增加。
刺激新生儿心脏的脂肪酸β-氧化可能是一种新的心脏保护干预措施，可限制缺血后收缩功能障碍。
