Changes in the Left Ventricular Eicosanoid Profile in Human Dilated Cardiomyopathy

Area of Science:

• Cardiovascular Research
• Metabolomics
• Mitochondrial Biology

Background:

• Polyunsaturated fatty acids (PUFAs) and their metabolites have complex roles in cardiac health.
• Mitochondrial dysfunction is a hallmark of dilated cardiomyopathy (DCM).
• The specific contribution of PUFA metabolites to DCM-associated mitochondrial dysfunction is not well understood.

Purpose of the Study:

• To investigate alterations in the polyunsaturated fatty acid (PUFA) metabolome in dilated cardiomyopathy (DCM).
• To assess the relationship between PUFA metabolite profiles and cardiac mitochondrial quality in human DCM explanted hearts.

Main Methods:

• Analysis of N-3 and N-6 PUFA metabolites in left ventricular tissues from non-failing controls (NFC) and DCM explanted hearts using LC-MS/MS.
• Quantification of mRNA and protein expression for key enzymes (CYP2J2, CYP2C8, epoxide hydrolases) involved in PUFA metabolism.
• Assessment of cardiac mitochondrial quality via transmission electron microscopy, respiratory chain complex activities, and oxygen consumption.

Main Results:

• Elevated levels of cardioprotective CYP-derived lipid mediators, epoxy fatty acids (EpFAs), and their diols were observed in DCM hearts.
• Increased expression of enzymes involved in PUFA metabolism (CYP2J2, CYP2C8, epoxide hydrolases) indicated enhanced metabolic flux.
• DCM hearts exhibited significant mitochondrial ultrastructural damage and impaired mitochondrial function, which was partially restored by exogenous EpFA administration.

Conclusions:

• Increased expression of CYP-epoxygenase enzymes and epoxide hydrolases in DCM hearts correlates with enhanced PUFA-derived EpFA turnover.
• Severe mitochondrial dysfunction in DCM can be linked to these metabolic alterations.
• Exogenous administration of EpFAs shows potential for rescuing mitochondrial function in DCM.