Hydrogen sulfide attenuates myocardial fibrosis in diabetic rats through the JAK/STAT signaling pathway

Abstract

The aim of the present study was to determine the role of hydrogen sulfide (H2S) in improving myocardial fibrosis and its effects on oxidative stress, endoplasmic reticulum (ER) stress and cell apoptosis in diabetic rats, by regulating the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway. A total of 40 male Sprague-Dawley rats were randomly divided into four groups (n=10) as follows: Normal (control group), diabetes mellitus [streptozotocin (STZ) group], diabetes mellitus treated with H2S (STZ + H2S group), and normal rats treated with H2S (H2S group). Diabetes in rats was induced by intra-peritoneal (i.p.) injection of STZ at a dose of 40 mg/kg. NaHS (100 µmol/kg, i.p.), which was used as an exogenous donor of H2S, was administered to rats in the STZ + H2S and H2S groups. After 8 weeks, the pathological morphological changes in myocardial fibers were observed following hematoxylin and eosin and Masson's trichrome staining. Apoptosis of myocardial tissue was analyzed by the terminal deoxynucleotidyl transferase dUTP nick end labeling assay. Oxidative stress was evaluated through detecting the content of malondialdehyde (MDA), 4-hydroxynonenal (4-HNE), glutathione (GSH) and superoxide dismutase (SOD) in the myocardial cells by ELISA. The expression of collagen III, matrix metalloproteinase (MMP)8, MMP14, tissue inhibitor of metalloproteinase (TIMP)2, transforming growth factor (TGF)-β, cystathionine-γ-lyase (CSE), eukaryotic initiation factor 2α (eIF2α), GRP94, Bcl-2, caspase-3, tumor necrosis factor (TNF)-α, nuclear factor-κB (NF-κB) and proteins related to the JAK/STAT pathway, was detected by western blot analysis. The results indicated that the array of myocardial cells was markedly disordered in STZ group rats; compared with the control group, both myocardial interstitial fibrosis and the deposition of collagen III were increased. Furthermore, the expression ratio of MMPs/TIMPs was dysregulated, while the expression levels of TGF-β, eIF2α, GRP94, caspase-3, TNF-α, NF-κB, MDA and 4-HNE were significantly increased. Furthermore, the expressions of JAK-1/2 and STAT1/3/5/6 were also markedly upregulated, while those of CSE, SOD, GSH and Bcl-2 were downregulated. Compared with the STZ group, these changes were reversed in the STZ + H2S group. The results of the present study demonstrated that H2S can improve myocardial fibrosis in diabetic rats, and the underlying mechanism may be associated with the downregulation of the JAK/STAT signaling pathway, thereby suppressing oxidative stress and ER stress, inflammatory reaction and cell apoptosis.

A high‐fat diet rich in corn oil induces cardiac fibrosis in rats by activating JAK2/STAT3 and subsequent activation of ANG II/TGF‐1β/Smad3 pathway: The role of ROS and IL‐6 trans‐signaling

“…*,**,*** : versus LFD-fed rats at p < 0.05, p < 0.1, and p < 0.001, respectively cells (Boengler et al, 2008;Marrero et al, 1995, Mascareno et al, 1998Modesti et al, 2005). Pharmacological inhibition of JAK2/ STAT3 or deletion of NAD(P)H oxidase in rodents' animal model inhibited cardiac hypertrophy and fibrosis and inhibited levels of TGF-β1and fibronectin synthesis in mesangial cells (Boengler et al, 2008;Byrne et al, 2003;Liu et al, 2018;Rosenkranz, 2004). In contrast, IL-6 induced hypertrophy and fibrosis in the heart of rats but the mechanism behind this remains not clearly identified (Meléndez et al, 2010).…”

“…In cardiac myocytes and fibroblasts, Ang II, through AT1 receptors, induces TGF‐β1 expression by direct activation of NAD(P)H oxidase‐induced activation of a JAK2/STAT3/STAT5 signaling pathway, which in turns creates an autocrine/paracrine loop to stimulate ANG II synthesis in adjacent cells (Boengler et al, ; Marrero et al, , Mascareno et al, ; Modesti et al, ). Pharmacological inhibition of JAK2/STAT3 or deletion of NAD(P)H oxidase in rodents' animal model inhibited cardiac hypertrophy and fibrosis and inhibited levels of TGF‐β1and fibronectin synthesis in mesangial cells (Boengler et al, ; Byrne et al, ; Liu et al, ; Rosenkranz, ). In contrast, IL‐6 induced hypertrophy and fibrosis in the heart of rats but the mechanism behind this remains not clearly identified (Meléndez et al, ).…”

“…Currently, much attention is given to vicious relation between ANG II and JAK/STAT signal transduction pathway during cardiac remodeling (Liu et al, 2018;Modesti et al, 2005;Wang et al, 2002;Wong et al, 2015). All STAT family members have been reported in mammalian's heart (Booz et al, 2003;Mascareno et al, 2001).…”

“…In contrast, the signaling pathway, Janus kinase/signal transducer and activator of transcription (JAK/STAT), was shown to be a master signaling pathway that is activated during cardiac fibrosis and remodeling. Indeed, the JAK/STAT pathway has been shown to be over-activated in fibrotic hearts of various models of CVD including those under pressure overload and induced-ischemia, myocardial infarction (MI), heart failure (HF), and diabetes mellitus (DM) (Boengler, Hilfikerkleiner, Drexler, Heusch, & Schulz, 2008;Liu et al, 2018;Mascareno et al, 2001;Modesti et al, 2005;Wang, Shaw, Amiri, Eaton, & Marrero, 2002;Wong, et al, 2015). The JAK/STAT family includes JAK1-3 and STAT1-4, STAT5a, STAT5b, and STAT6, all of which have been observed in the mammalian's heart or neonatal ventricular myocytes (Booz, Day, & Baker, 2003).…”

Hydrogen sulfide attenuates paraquat‐induced epithelial‐mesenchymal transition of human alveolar epithelial cells through regulating transforming growth factor‐β1/Smad2/3 signaling pathway

“…The irreversible and progressive pulmonary fibrosis leading to respiratory function failure is still the main cause of PQ‐induced death (Dinis‐Oliveira et al, ). Recently, increasing evidence indicates that plasma H 2 S is low level in several animal models of fibrotic diseases and a supplement of exogenous H 2 S is able to ameliorate fibrosis in the kidney (Han et al, ; L. Li et al, ; Li, Li, Zeng, Liu, & Yang, ), heart (Li et al, ; Liang et al, ; Liu et al, ), liver (Mani, Cao, Wu, & Wang, ), peritoneum (Lu et al, ), skin and lung (Fang et al, ; Wang et al, ). As a significant process towards fibrogenesis, EMT characterizes the morphological changes associated with the downregulation of epithelial cell markers, such as E‐cadherin, and upregulation of mesenchymal markers, such as vimentin (Cannito et al, ).…”