Altered Cardiolipin Metabolism is Associated with Cardiac Mitochondrial Dysfunction in Pulmonary Vascular Remodeled Perinatal Rat Pups

Abstract

AbstractBackgroundPulmonary vascular remodeling (PVR) in utero results in the development of heart failure (HF). The alterations that occur in cardiac lipid and mitochondrial bioenergetics during the development of in utero PVR was unknown.MethodsPVR was induced in pups in utero by exposure of pregnant dams to indomethacin and hypoxia. Cardiac lipids, echocardiographic function and cardiomyocyte mitochondrial function were subsequently examined.ResultsPerinatal rat pups with PVR exhibited elevated left and right cardiac ventricular internal dimensions and reduced ejection fraction and fractional shortening compared to controls. Cardiac myocytes from these pups exhibited increased glycolytic capacity and glycolytic reserve compared to controls. However, respiration with glucose as substrate was unaltered. Fatty acid oxidation and ATP-insensitive respiration were increased in isolated cardiac myocytes from these pups compared to controls indicating mitochondrial dysfunction. Although abundance of mitochondrial respiratory complexes were unaltered, increased trilinoleoyl-lysocardiolipin levels in these pups was observed. A compensatory increase in both cardiolipin (CL) and phosphatidylethanolamine (PE) content were observed due to increased synthesis of these phospholipids.ConclusionAlterations in cardiac cardiolipin and phospholipid metabolism in PVR rat pups is associated with the mitochondrial bioenergetic and cardiac functional defects observed in their hearts.Impact statement- Phospholipid metabolism was examined in pulmonary vascular remodeling in perinatal rat pups.- Pulmonary vascular remodeling was induced in utero by treating pregnant dams with hypoxia and indomethacin at 19-21 days of gestation.- The offspring exhibited altered pulmonary arterial remodeling with subsequent cardiac hypertrophy, ventricular dysfunction, cardiac myocyte mitochondrial dysfunction with altered fatty acid utilization.- In addition, the offspring exhibited elevated cardiolipin, lysocardiolipin and phosphatidylethanolamine content which may potentially contribute to the cardiac mitochondrial dysfunction.