Bempedoic acid induces minimal transcriptomic and proteomic alterations in rat cardiac tissue

While lipid-lowering medications like statins offer some cardiac protection, they may also carry hidden cardiotoxic risks (Ferdinandy et al., 2014, 2019). Our previous study showed that bempedoic acid (BA), a new lipid-lowering drug, neither harmed nor protected heart tissue in a rat model of acute myocardial infarction, though it slightly reduced arrhythmias caused by reperfusion (Gergely et al., 2023). However, its direct impact on the transcriptomic and proteomic profile of the heart and other tissues after treatment remains unexplored.

This study aimed to explore changes in gene expression and protein profiles in the left ventricle (LV), liver, and adipose tissue following chronic BA administration in vivo.

In prior experiments, male Wistar rats were treated with BA (30 mg/kg) or vehicle for 28 days. Some rats underwent 30 minutes of left anterior descending artery occlusion followed by 120 minutes of reperfusion to induce ischemia/reperfusion (I/R) injury, while others were sham-operated. LV, liver, and adipose tissues were collected for RNA sequencing. Proteomic and phosphoproteomic analyses were performed in the LV. Gene ontology (GO) analysis characterized the differentially expressed genes.

In sham-operated rats, BA altered the expression of 63 genes in LV tissue (50 upregulated, 13 downregulated), mainly related to cellular metabolism. Proteomics confirmed the expression changes in four genes, namely Mpc2, Pfdn2, Tpm, and Mlycd. BA treatment induced the dephosphorylation of Gys1, Ctnna1, Uba2, Cavin1, Cr1l, Ank1 and Ttn proteins in the LV. Following I/R, BA altered the expression of Lrpprc, Cfd and Lsm10 genes in the LV. The liver exhibited widespread transcriptomic shifts, with 432 genes affected. GO analysis revealed that these genes are primarily involved in cholesterol and lipid metabolism. The adipose tissue showed changes in 30 genes related mainly to stress response.

Bempedoic acid’s most pronounced effects on gene expression occur in the liver, aligning with its known lipid-lowering action, while its impact on cardiac tissue gene expression is minimal.