Cyclophilin D inhibition rescues cardiac function in neonatal hypoxia.

Abstract

The heart develops in utero under hypoxic conditions, and exposure to higher oxygen levels at birth activates changes in the heart to allow survival ex-utero. Mitochondria are critical in terminal cardiac myocyte differentiation after birth, and inhibition of the mitochondrial chaperone cyclophilin D (CypD) enhances this process by regulating the electron transport chain (ETC) to meet increased metabolic demands. Disruption of this process may play a role in neonatal cardiomyopathy and congenital heart disease. We tested the hypothesis that inhibition of CypD with cyclosporin A (CsA) or N-methyl-4-isoleucine cyclosporin (NIM811) will rescue the effects of hypoxia on cardiac and mitochondrial function. Mice were exposed to hypoxia (12% oxygen) immediately before birth (gestational age E19.5) to postnatal day 7 (P7). Hypoxic mice received no treatment (NoTx) or intraperitoneal injections 10mg/kg of vehicle, CsA, or NIM811 from P1 to P6. Room air neonates served as controls. On P7, mice underwent echocardiography and hearts were harvested for mitochondrial isolation for various assays of mitochondrial structure and function. Hypoxia decreased survival and body weight, caused cardiomegaly, decreased cellular organization, and decreased cardiac function in the NoTx and vehicle groups when compared to room air controls, while the enzymatic function of ETC complexes I and III (P<0.01) and complex I-mediated respiration (P<0.0001) was decreased. Treatment with CsA and NIM811 normalized cardiomegaly, cardiac function, cellular structure, ETC activity of complexes I and III and the mitochondrial respiratory capacity for complex I. Thus, pharmacologic inhibition of CypD reversed the effects of hypoxia on ETC activity and overall cardiac function and structurein the neonatal heart. Our study may help develop therapies to treat cardiomyopathies and the effects of hypoxia on the neonatal heart.