Granulocyte colony-stimulating factor attenuates myocardial remodeling and ventricular arrhythmia susceptibility via the JAK2-STAT3 pathway in a rabbit model of coronary microembolization

Abstract

Background: Coronary microembolization (CME) has a poor prognosis, with ventricular arrhythmia being the most serious consequence. Understanding the underlying mechanisms could improve its management. We investigated the effects of granulocyte colony-stimulating factor (G-CSF) on connexin-43 (Cx43) expression and ventricular arrhythmia susceptibility after CME. Methods: Forty male rabbits were randomized into four groups (n = 10 each): Sham, CME, G-CSF, and AG490 (a JAK2 selective inhibitor). Rabbits in the CME, G-CSF, and AG490 groups underwent left anterior descending (LAD) artery catheterization and CME. Animals in the G-CSF and AG490 groups received intraperitoneal injection of G-CSF and G-CSF + AG490, respectively. The ventricular structure was assessed by echocardiography. Ventricular electrical properties were analyzed using cardiac electrophysiology. The myocardial interstitial collagen content and morphologic characteristics were evaluated using Masson and hematoxylin-eosin staining, respectively. Results: Western blot and immunohistochemistry were employed to analyze the expressions of Cx43, G-CSF receptor (G-CSFR), JAK2, and STAT3. The ventricular effective refractory period (VERP), VERP dispersion, and inducibility and lethality of ventricular tachycardia/fibrillation were lower in the G-CSF than in the CME group (P < 0.01), indicating less severe myocardial damage and arrhythmias. The G-CSF group showed higher phosphorylated-Cx43 expression (P < 0.01 vs. CME). Those G-CSF-induced changes were reversed by A490, indicating the involvement of JAK2. G-CSFR, phosphorylated-JAK2, and phosphorylated-STAT3 protein levels were higher in the G-CSF group than in the AG490 (P < 0.01) and Sham (P < 0.05) groups. Conclusion: G-CSF might attenuate myocardial remodeling via JAK2-STAT3 signaling and thereby reduce ventricular arrhythmia susceptibility after CME.

Granulocyte Colony-Stimulating Factor Treatment Before Radiotherapy Protects Against Radiation-Induced Liver Disease in Mice

“…The beneficial effects of G-CSF in the treatment of various injuries, including bone fracture healing ( Moukoko et al, 2018 ), thin endometrium and recurrent implantation failure ( Kamath et al, 2017 ), leukemia ( Feng et al, 2018 ), and other diseases such as cardiovascular diseases ( D’Amario et al, 2018 ) have been shown. According to Wang et al (2020) , G-CSF was able to reduce infarction size and interstitial collagen fiber deposition in the myocardium, attenuating myocardial remodeling and ventricular arrhythmia in a rabbit model of coronary microembolization. These studies have demonstrated that the mobilization mechanism is related to its capacity to stimulate cell migration and promote anti-apoptotic and anti-inflammatory properties.…”

Identification of novel prognostic targets in coronary artery disease and related complications using bioinformatics and next generation sequencing data analysis

“…DOCK4 [58], CEACAM1 [59], STAT1 [60], ARG1 [61], TLR4 [62], ADAM9 [63], VNN1 [64], ABCA1 [65], STAT2 [66], TLR5 [67], PTGS2 [68], RNF213 [69], ZDHHC17 [70], JAK2 [71], TLR8 [72], NOTCH2 [73], PDGFC (platelet derived growth factor C) [74], CMPK2 [75], TLR2 [76], CYP1B1 [77], CCR1 [78], HDAC9 [79], IL1RN [80], GCH1 [81], LYST (lysosomal trafficking regulator) [82], PELI1 [83], EGR1 [84], SNX10 [85], CA2 [86], ZEB2 [87], HIF1A [88], PLA2G7 [89], CCR2 [90], GAB1 [91], IRAK3 [92], LDLR (low density lipoprotein receptor) [93], TLR6 [94], SIRT1 [95], NOD2 [96], ATP10D [97], ELOVL6 [98], VCAN (versican) [99], TET2 [100], TET3 [101], ZBTB20 [102], HS3ST1 [103], PF4 [104], DNAJC2 [105], NFIA (nuclear factor I A) [106], CCR7 [107], PRDX2 [108], ADK (adenosine kinase) [109], TCF7 [110], LGALS3 [111], OLFM2 [112], HDAC11 [113] and ARPC1B [114] are significantly related to the atherosclerosis. Studies have revealed that KCNJ2 [115], TLR4 [116], JAK2 [117], TLR2 [118], EGR1 [119], GAB1 [120], ZBTB11 [121], BIN1 [122], TCF4 [123], PPP1R13L [124], TRPM4 [125], LGALS3 [126] and SNTA1 [127] plays a key role in cardiac arrhythmia. Recently, increasing evidence demonstrated that KCNJ2 [128], TLR4 [129], CYP2D6 [130], TLR2 [129], SNX10 [131], SIRT1 [132<...…”

Post-myocardial infarction fibrosis: Pathophysiology, examination, and intervention

“…In the macrophage protease-activated receptor two knockout mice, there are down-regulation of proinflammatory cytokines, recruitment of macrophages, fibrosis in a remote area, and macrophage-derived interferon-β expression, which stimulate the JAK/STAT3 pathway in CFs ( Zuo et al, 2020 ). In addition, granulocyte colony-stimulating factor (G-CSF) improves cardiac remodeling by upregulating JAK2/STAT3 axis ( Wang et al, 2020h ). Further, N-Propargyl caffeate amide promotes pro-resolving macrophage polarization and prevents cardiac fibrosis by activating peroxisome proliferator-activated receptors-γ (PPAR-γ) pathway ( Cheng et al, 2020 ).…”