Crenigacestat

FSTL1-USP10-Notch1 Signaling Axis Protects Against Cardiac Dysfunction Through Inhibition of Myocardial Fibrosis in Diabetic Mice

Abstract

The global incidence of type 2 diabetes mellitus (T2DM) is rising, and individuals with T2DM face an elevated risk of severe cardiac events, such as myocardial infarction (MI). However, the molecular mechanisms behind MI-related damage in T2DM are not yet fully understood. Ubiquitin-specific protease 10 (USP10) acts as a deubiquitinase for NICD1 (Notch1 receptor), which is crucial for regulating myocardial fibrosis through Notch signaling. Follistatin-like protein 1 (FSTL1) is a cardiokine known to have beneficial effects on various pathological conditions, including cardiac fibrosis and insulin resistance. This study aimed to investigate the roles of FSTL1/USP10/Notch1 signaling in cardiac dysfunction caused by MI in the context of T2DM.

We used 8-week-old C57BL/6J mice on a high-fat diet and db/db T2DM mice for our experiments. Following MI surgery, we administered AAV9-FSTL1 intracardially to T2DM mice, with or without intraperitoneal injections of crenigacestat (LY3039478) and spautin-1. Our results showed that FSTL1 improved cardiac function after MI in T2DM by decreasing serum lactate dehydrogenase (LDH) levels, reducing myocardial apoptosis, and alleviating cardiac fibrosis. Further in vivo studies revealed that FSTL1′s protective effect against MI injury in T2DM was mediated through the activation of USP10/Notch1 signaling. FSTL1 safeguarded cardiac fibroblasts from damage caused by DM-MI by lowering fibrosis marker levels and reducing LDH and MDA concentrations in a USP10/Notch1-dependent manner.

In conclusion, FSTL1 treatment improved cardiac function in the context of MI with concurrent T2DM, likely by inhibiting myocardial fibrosis and apoptosis through upregulation of USP10/Notch1 signaling. These findings highlight the potential clinical relevance and therapeutic promise of FSTL1 for treating MI associated with T2DM and other cardiovascular Crenigacestat diseases.