Persistent pulmonary hypertension results in reduced tetralinoleoyl-cardiolipin and mitochondrial complex II + III during the development of right ventricular hypertrophy in the neonatal pig heart

Abstract

Persistent pulmonary hypertension of the newborn (PPHN) results in right ventricular (RV) hypertrophy followed by right heart failure and an associated mitochondrial dysfunction. The phospholipid cardiolipin plays a key role in maintaining mitochondrial respiratory and cardiac function via modulation of the activities of enzymes involved in oxidative phosphorylation. In this study, changes in cardiolipin and cardiolipin metabolism were investigated during the development of right heart failure. Newborn piglets (<24 h old) were exposed to a hypoxic (10% O(2)) environment for 3 days, resulting in the induction of PPHN. Two sets of control piglets were used: 1) newborn or 2) exposed to a normoxic (21% O(2)) environment for 3 days. Cardiolipin biosynthetic and remodeling enzymes, mitochondrial complex II + III activity, incorporation of [1-(14)C]linoleoyl-CoA into cardiolipin precursors, and the tetralinoleoyl-cardiolipin pool size were determined in both the RV and left ventricle (LV). PPHN resulted in an increased heart-to-body weight ratio, RV-to-LV plus septum weight ratio, and expression of brain naturetic peptide in RV. In addition, PPHN reduced cardiolipin biosynthesis and remodeling in the RV and LV, which resulted in decreased tetralinoleoyl-cardiolipin levels and reduced complex II + III activity and protein levels of mitochondrial complexes II, III, and IV in the RV. This is the first study to examine the pattern of cardiolipin metabolism during the early development of both the RV and LV of the newborn piglet and to demonstrate that PPHN-induced alterations in cardiolipin biosynthetic and remodeling enzymes contribute to reduced tetralinoleoyl-cardiolipin and mitochondrial respiratory chain function during the development of RV hypertrophy. These defects in cardiolipin may play an important role in the rapid development of RV dysfunction and right heart failure in PPHN.

Impaired Cardiolipin Biosynthesis Prevents Hepatic Steatosis and Diet-Induced Obesity

“…In previous studies mitochondrial dysfunction occurred in the liver when CL and/or L 4 CL levels were reduced by >35% (32,33). Similar reductions in CL have also accompanied mitochondrial dysfunction in the myocardium (6,8). In our recent study using heterozygous Mtpa knockout mice, small reductions (∼25–30%) in CL and L 4 CL in the heart and liver were found to have no effect on supercomplexes in either tissue (34).…”

“…Loss of CL and/or L 4 CL has been widely demonstrated in human and animal models of heart failure (4,6–8). One way in which CL content regulates mitochondrial dysfunction is through direct involvement in the assembly and function of respiratory supercomplexes (4).…”

“…Induced pluripotent stem cells developed from patients with BTHS have decreased supercomplex formation, which coincides with reduced oxygen consumption and increased generation of ROS (10). Indeed, loss of CL content in heart failure is associated with reduced activity of individual respiratory complexes and impaired mitochondrial respiratory function (6,8). …”

Cardiolipin fatty acid remodeling regulates mitochondrial function by modifying the electron entry point in the respiratory chain

“…Abnormalities in CL fatty acid composition have been reported in multiple disorders such as pulmonary hypertension (Saini-Chohan et al , 2011), heart failure (Sparagna et al , 2007 and Saini-Chohan et al , 2009), acute myocardial ischemia and reperfusion (Lesnefsky et al , 2001 and Petrosillo et al , 2003), and both insulin- and non insulin-dependent diabetes mellitus (Han et al , 2005 and Han et al , 2007). These modifications of CL levels or fatty acid composition are associated with changes in mitochondrial function (Petrosillo et al , 2003 and Heather et al , 2010).…”

Exogenous arachidonic acid mediates permeability of human brain microvessel endothelial cells through prostaglandin E2 activation of EP3 and EP4 receptors

“…The samples were heated in the thermal cycler for 15 min at 95°C for reverse transcription, followed by 40 cycles of denaturation at 95°C for 15 s, annealing at 60°C for 30 s and extension at 72°C for 30 s. Relative gene expression was determined as previously described with 18S rRNA as control and represented as fold‐change compared to 18S rRNA (Saini‐Chohan et al . ). Primers used for the analysis are shown in Table .…”