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

Abstract

The incidence of type 2 diabetes mellitus (T2DM) has been increasing globally, and T2DM patients are at an increased risk of major cardiac events such as myocardial infarction (MI). Nevertheless, the molecular mechanisms underlying MI injury in T2DM remain elusive. Ubiquitin-specific protease 10 (USP10) functions as a NICD1 (Notch1 receptor) deubiquitinase that fine-tunes the essential myocardial fibrosis regulator Notch signaling. Follistatin-like protein 1 (FSTL1) is a cardiokine with proven benefits in multiple pathological processes including cardiac fibrosis and insulin resistance. This study was designed to examine the roles of FSTL1/USP10/Notch1 signaling in MI-induced cardiac dysfunction in T2DM. High-fat-diet-treated, 8-week-old C57BL/6J mice and db/db T2DM mice were used. Intracardiac delivery of AAV9-FSTL1 was performed in T2DM mice following MI surgery with or without intraperitoneal injection of crenigacestat (LY3039478) and spautin-1. Our results demonstrated that FSTL1 improved cardiac function following MI under T2DM by reducing serum lactate dehydrogenase (LDH) and myocardial apoptosis as well as cardiac fibrosis. Further in vivo studies revealed that the protective role of FSTL1 against MI injury in T2DM was mediated by the activation of USP10/Notch1. FSTL1 protected cardiac fibroblasts (CFs) against DM-MI-induced cardiofibroblasts injury by suppressing the levels of fibrosis markers, and reducing LDH and MDA concentrations in a USP10/Notch1-dependent manner. In conclusion, FSTL1 treatment ameliorated cardiac dysfunction in MI with co-existent T2DM, possibly through inhibition of myocardial fibrosis and apoptosis by upregulating USP10/Notch1 signaling. This finding suggests the clinical relevance and therapeutic potential of FSTL1 in T2DM-associated MI and other cardiovascular diseases.

USP14 regulates ATF2/PIK3CD axis to promote microvascular endothelial cell proliferation, migration and angiogenesis in diabetic retinopathy

“…The UPS family possesses an important function in maintaining protein homeostasis and is associated with diabetes-related complications (21,22). In the study of type 2 diabetes, Forand et al found that inhibiting the dissociation of USP7/Insulinreceptorsubstrate1 (IRS1) and preventing the ubiquitination of IRS1 had a protective effect on diabetic mice (23).…”

Ubiquitin-Specific Proteases (USPs) and Metabolic Disorders

“…T2DM patients have an increased risk of several cardiac disorders, including myocardial infarction (MI) [ 175 ]. Interestingly, in T2DM models induced by a high-fat diet or leptin receptor deficiency, the left ventricular rejection fraction and left ventricular fraction shortening were decreased, while the ventricular internal diameter at end-diastole and the left ventricular internal diameter at end-systole were increased [ 176 ]. Moreover, additional treatment with MI caused further alterations in these indices [ 176 ].…”

“…Interestingly, in T2DM models induced by a high-fat diet or leptin receptor deficiency, the left ventricular rejection fraction and left ventricular fraction shortening were decreased, while the ventricular internal diameter at end-diastole and the left ventricular internal diameter at end-systole were increased [ 176 ]. Moreover, additional treatment with MI caused further alterations in these indices [ 176 ]. In T2DM models, increases were found in α-smooth muscle actin, a myofibroblast marker, and the fibrosis markers collagen type I and matrix metalloprotease 9, suggesting the occurrence of cardiac fibrosis [ 176 ].…”

Exercise-induced signaling pathways to counteracting cardiac apoptotic processes

“…While moderate physical activity increases the coronary arteries and capillary density in wild-type mice and capillary density does not change in mice without Notch3 ( Ragot et al, 2016 ). Increased exercise (56–66% of VO 2max for 4 weeks)-induced Follistatin-like protein 1 (FSTL1) secretion through the FSTL1-USP10-Notch1 signaling axis has been reported to inhibit myocardial fibrosis in diabetic rats ( Xi et al, 2016 ; Lu et al, 2021 ) ( Table 2 ). Aerobic exercise (75% of maximal metabolic for 12 weeks) significantly reduces systolic blood pressure, which is independently correlated with skin capillary density and vascular density in humans.…”

“…Increase (Burgess et al, 2001;Burgess et al, 2002;Brancaccio et al, 2006;Wilkinson et al, 2008;Manso et al, 2009;Flueck et al, 2011;Muthuchamy et al, 2012;Li et al, 2013;Watson and Baar, 2014;Graham et al, 2015a;Graham et al, 2015b;Franchi et al, 2018) Aerobic exercise 56-66% of VO2max for 4 weeks FSTL1-USP10-Notch1, Notch3, sFLT1 Increase (Xi et al, 2016;Lu et al, 2021) Aerobic exercise 75% of maximal metabolic for 12 weeks Notch1/Akt/eNOS Increase Liang et al (2021) Aerobic exercise 75% of VO2max for 6 weeks SIRT1, MnSOD, PGC-1α, HIF-1α, VEGF, catalase Increase (Rinaldi et al, 2013;Wen et al, 2019) Swimming training 48-72% of VO2max for 5 weeks…”