SREBP1 induction mediates long-term statins therapy related myocardial lipid peroxidation and lipid deposition in TIIDM mice

Statins therapy is efficacious in diminishing the risk of major cardiovascular events in diabetic patients. However, our research has uncovered a correlation between the prolonged administration of statins and an elevated risk of myocardial dysfunction in patients with type II diabetes mellitus (TIIDM). Here, we report the induction of sterol regulatory element-binding protein 1 (SREBP1) activation, associated lipid peroxidation, and the consequent diabetic myocardial dysfunction after statin treatment and explored the underlying mechanisms. In db/db mice, we observed that 40 weeks atorvastatin (5 and 10 mg/kg) and rosuvastatin (20 mg/kg) administration exacerbated diabetic myocardial dysfunction by echocardiography and cardiomyocyte contractility assay, increased myocardial inflammation and fibrosis as shown by CD68, IL-1β, Masson's staining and Collagen1A1 immunohistochemistry (IHC) staining, increased respiratory exchange ratio (RER) by metabolic cage system assessment, exacerbated mitochondrial structural pathological changes by transmission electron microscopy (TEM) examination, increased deposition of lipid and glycogen by TEM, Oil-red and periodic acid-schiff stain (PAS) staining, which were corresponded with augmented levels of myocardial SREBP1 protein and lipid peroxidation marked by 4-hydroxynonenal (4-HNE) staining. Comparable myocardial fibrosis was also observed in KK-ay and low-dose streptozotocin (STZ)-induced TIIDM mice. Elevated SREBP1 levels were observed in the heart tissues from diabetic patients, which was positively correlated with their myocardial dysfunction. To elucidate the role of statin induced SREBP1 in lipid peroxidation and lipid deposition and related mechanism, we cultured neonatal mouse primary cardiomyocytes (NMPCs) and treated them with atorvastatin (10 μM, 24 h), tracing with [U-