Victoria H Lam1, Liyan Zhang1, Alda Huqi1, Arata Fukushima1, Brandon A Tanner1, Arzu Onay-Besikci1, Wendy Keung1, Paul F Kantor1, Jagdip S Jaswal1, Ivan M Rebeyka1, Gary D Lopaschuk2. 1. 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.). 2. 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.). gary.lopaschuk@ualberta.ca.
Abstract
RATIONALE: 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. OBJECTIVE: 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. METHODS AND RESULTS: 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. CONCLUSIONS: Stimulating fatty acid β-oxidation in neonatal hearts may present a novel cardioprotective intervention to limit post-ischemic contractile dysfunction.
RATIONALE: 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. OBJECTIVE: 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. METHODS AND RESULTS: 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. CONCLUSIONS: Stimulating fatty acid β-oxidation in neonatal hearts may present a novel cardioprotective intervention to limit post-ischemic contractile dysfunction.
Authors: Arata Fukushima; Liyan Zhang; Alda Huqi; Victoria H Lam; Sonia Rawat; Tariq Altamimi; Cory S Wagg; Khushmol K Dhaliwal; Lisa K Hornberger; Paul F Kantor; Ivan M Rebeyka; Gary D Lopaschuk Journal: JCI Insight Date: 2018-05-17
Authors: Yan Huang; Corey Powers; Victoria Moore; Caitlin Schafer; Mindong Ren; Colin K L Phoon; Jeanne F James; Alexander V Glukhov; Sabzali Javadov; Frédéric M Vaz; John L Jefferies; Arnold W Strauss; Zaza Khuchua Journal: Orphanet J Rare Dis Date: 2017-03-09 Impact factor: 4.123
Authors: Caitlin Schafer; Vicky Moore; Nupur Dasgupta; Sabzali Javadov; Jeanne F James; Alexander I Glukhov; Arnold W Strauss; Zaza Khuchua Journal: Front Pharmacol Date: 2018-04-11 Impact factor: 5.810