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.
Highlights
The prevalence of diabetes mellitus (DM) worldwide is increasing, and it is estimated to reach 693 million patients by 2045
LVIDd and LVIDs were slightly increased in diabetic mice (Figures 2D–E), along with increased body weight, heart weight, and heart weight to body weight ratio (Figures 2F–H), The above parameters, excepting body weight were further increased in type 2 diabetes mellitus (T2DM) mice post-myocardial infarction (MI)
The present study revealed that Follistatin-like protein 1 (FSTL1) and Ubiquitin-specific protease 10 (USP10) were significantly activated in T2DM mice with MI, and FSTL1 treatment further increased USP10 activation and alleviating cardiac dysfunction by reducing myocardial fibrosis
Summary
The prevalence of diabetes mellitus (DM) worldwide is increasing, and it is estimated to reach 693 million patients by 2045. Diet and exercise represent a practical avenue for the treatment and prevention of type 2 diabetes mellitus (T2DM) (Magkos et al, 2020; Reynolds et al, 2020), coronary ischemic heart diseases are considered the main causes of heart failure and mortality in patients with DM (Del Re et al, 2019; Dillmann 2019). Myocardial infarction (MI) is one of the major cardiac sequelae in patients with DM, accompanied by mitochondrial dysfunction, inflammation, apoptosis, and myocardial fibrosis (Birnbaum et al, 2019; Lu et al, 2020a; Frangogiannis 2020; Wu et al, 2021). Follistatin-like protein 1 (FSTL1) is a secreted cardiokine glycoprotein that belongs to the follistatin family, the levels of which are upregulated in the stressed heart (Ogura et al, 2012; Maruyama et al, 2016). The role of FSTL1 in MI-induced cardiac remodeling in the setting of T2DM has not been elucidated
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