Abnormalities of Cardiolipin Synthesis and Remodeling in Heart Failure: A Cornerstone of Energy Deprivation

Mitochondrial (MITO) abnormalities and energy deprivation occur in heart failure (HF). Cardiolipin (CL) is the signature lipid of the MITO inner membrane, site for the electron transport chain (ETC). CL plays a key role in MITO biogenesis, fission and fusion, and respiration and, as such, is essential for oxidative phosphorylation. Increased production of reactive oxygen species (ROS) occurs in HF and can trigger CL peroxidation, thus damaging the MITO inner membrane. We and others showed that HF is associated with abnormal MITO biogenesis, fission and fusion and respiration. This study examined changes in the extent of ROS formation, 4-hydroxynonenal (4-HNE), a bi-product of lipid peroxidation, CL levels, CL synthase (CLS), a key enzyme in the synthesis of CL, level of the CL remodeling enzyme tafazzin-1 (TAZ1), and maximum rate of ATP synthesis (ATPmax) in LV myocardium of normal (NL) dogs and dogs with chronic HF.

Studies were performed in LV tissue from NL dogs and dogs with HF produced by coronary microembolizations. Total ROS was measured using the luminol-dependent chemiluminescence assay and 4-HNE using an ELISA kit. Total CL and (18:2)₄CL species were measured using mass spectroscopy. TAZ1 level was measured by Western blotting, and ATPmax using a bioluminescent assay kit. CLS mRNA was quantifies using RT-PCR.

Compared to NL, ROS and 4-HNE significantly increased in HF dogs while total CL and (18:2)₄CL decreased. These abnormalities in HF dogs were accompanied by a 2.2 fold reduction in CLS mRNA expression, and significant reductions in TAZ1 protein level and ATPmax compared to NL.

In conclusion, the failing heart manifests marked abnormalities in the abundance, re-synthesis and remodeling of CL, a key regulator of energy metabolism. Excessive levels of ROS in HF may be important contributors to CL abnormalities. CL and its synthesis and remodeling elements are potential therapeutic targets for the treatment of HF.