Suppression of Post-Ischemic Cardiac Remodelling and Inflammatory Response by a Novel Sphingolipid Modifier, CIN038.

In patients with myocardial infarction (MI), the level of sphingolipids, such as ceramide (Cer), is elevated and is associated with an increased risk of progression towards heart failure (HF). Dihydroceramide desaturase 1 (DES1) catalyses the conversion of dihydroceramide (dhCer) into Cer in the de novo sphingolipid pathway. While pharmacological inhibition of DES1 has shown therapeutic benefits in metabolic disease and cancer models, its role in cardiac remodelling remains unclear. This study aimed to determine whether pharmacological inhibition of DES1 using the novel compound, CIN038, attenuates cardiac remodelling following ischemia-reperfusion (I/R) injury. Three-month-old male C57Bl/6 mice underwent I/R or sham surgery (n = 8) and were treated with vehicle or CIN038 (50 mg/kg/day, i.p.) for 28 days. Cardiac function, molecular changes, and lipid profiles in circulation and liver were assessed at the endpoint. CIN038 reduced infarct size and cardiac myocyte hypertrophy compared to the I/R + vehicle group. Profibrotic signalling was reduced in the infarcted hearts, as evidenced by reduced expression of Col1a1, Col3a1, and Tgfb mRNA and decreased levels of α-SMA and TGFβ1 protein expression. Inflammatory signalling was attenuated with reduced ERK and NFkB phosphorylation and suppression of Il-6-STAT axis. Despite these structural and molecular improvements, no changes were observed in cardiac function. Lipidomic analysis revealed selective alterations in circulating and hepatic lipid species, including plasmalogen phosphatidylethanolamines and ether-linked triglycerides, suggesting modulation of lipid metabolism. Collectively, these findings indicate that CIN038 attenuates post-ischemic cardiac remodelling by suppressing inflammatory and profibrotic signalling, highlighting DES1 as a potential therapeutic target following MI.