Ceramide Synthase 2 Promotes Cardiac Very-Long-Chain Dihydroceramide Accumulation and Is Linked to Arrhythmias and Heart Failure in Humans

TL;DR

This study shows that a specific enzyme, Ceramide Synthase 2, contributes to dangerous lipid buildup in heart cells during low oxygen, which may lead to arrhythmias and heart failure.

Contribution

The study identifies CerS2 as a novel driver of VLC-dihydroceramide accumulation in hypoxic heart cells, linking it to human cardiac disease.

Findings

Hypoxia causes accumulation of very-long-chain dihydroceramides in cardiomyocytes.

High levels of VLC-dihydroceramides in human heart tissue correlate with arrhythmias and heart failure.

Reducing CerS2 activity lowers VLC-dihydroceramide levels and affects calcium and electrical signaling in heart cells.

Abstract

Acute myocardial hypoxia/ischemia is associated with abnormal accumulation of myocardial lipids, including dihydroceramides. Here, we characterized how dihydroceramides are remodeled in response to hypoxia and assessed how dihydroceramide remodeling correlates to human cardiac pathophysiology. Hypoxia resulted in a marked accumulation of very-long-chain (VLC)-dihydroceramides in cultured HL-1 cardiomyocytes. In humans, we identified a correlation between the abundance of VLC-dihydroceramides in myocardial biopsies and arrhythmias and heart failure and showed that cardiac expression of CERS2, coding for an enzyme that promotes synthesis of VLC-dihydroceramides, was associated with signaling pathways linked to cardiac arrhythmia and cardiomyopathy. In cultured HL-1 cardiomyocytes, we showed that CerS2 knockdown reduced accumulation of VLC dihydroceramides and altered the expression of mediators regulating Ca2+ cycling and electrical conduction. In conclusion, our findings indicate that increased abundance of VLC-dihydroceramides, promoted by increased activity of CerS2 in response to hypoxia, could play a role in cardiac arrhythmias and heart failure.

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