Deciphering the Role of Different Ceramide Synthases in the Human Cardiomyocyte Hypertrophic Response

<b>Background/Objectives</b>: Recent studies suggest that plasma ceramide levels may be better predictors of CVD risk than LDL cholesterol. Ceramides are part of the sphingolipid class of lipids and are the central intermediates in complex sphingolipid biosynthesis. Sphingolipids are crucial for cellular structure and have important biological roles as complex signaling lipids, structurally and functionally differentiated by their acylated fatty acid. Higher plasma concentrations of 16:0 ceramide are associated with increased risk of heart failure. In contrast, higher concentrations of 22:0 plus 24:0 ceramide are associated with lower risk. We aim to address how alterations in these lipids can affect the human cardiac hypertrophic response. <b>Methods</b>: We silenced the ceramide synthase genes (<i>CERS</i>) responsible for the production of 16:0 ceramide (<i>CERS5</i>/<i>6</i>) or 22:0 and 24:0 ceramide (<i>CERS2</i>) in immortalized human ventricular cardiomyocytes and examined the altered cardiac hypertrophic response to phorbol 12-myristate 13-acetate treatment by examining changes in the transcriptome. <b>Results</b>: We discovered that silencing <i>CERS2</i> or <i>CERS5</i>/<i>6</i> drastically altered the cardiac cell hypertrophic response. We demonstrated that human cardiomyocytes with silenced <i>CERS2</i> appeared to have an exacerbated hypertrophy response, while cardiomyocytes with silenced <i>CERS5</i>/<i>6</i> had a more favorable response, suggesting that <i>CERS2</i> and <i>CERS5</i>/<i>CERS6</i> and their gene product metabolites may have opposing roles in the development and progression of CVD. <b>Conclusions</b>: The exact mechanisms through which various ceramides contribute to CVD progression are still unknown. This study will help elucidate the role of specific ceramides during cardiac hypertrophy and suggests that drugs targeting specific sphingolipids can potentially be a viable treatment option for the prevention of CVD.