Connective tissue growth factor dependent collagen gene expression induced by MAS agonist AR234960 in human cardiac fibroblasts

Chatterjee, Arunachal; Barnard, John; Moravec, Christine S.; Desnoyer, Russell; Tirupula, Kalyan; Karnik, Sadashiva S.

doi:10.1371/journal.pone.0190217

Cited by 6 publications

(3 citation statements)

References 38 publications

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“…Extracellular matrix remodeling during myocardial hypertrophy involves multiple enzymes and structural proteins (32), and our current study identified changes in RV FN, CTGF, COL1A1, and pulmonary FN without changes in collagen III or collagen IV. This may be due to a differential cardiac fibroblast synthetic response to hypertrophic stimuli (6,16,41,55). Our results are consistent with an important role for COL1A1 in PAH-associated RV fibrosis identified using a COL1A1 mutant mouse model that has attenuated RV fibrosis and dysfunction (69).…”

Section: Discussionsupporting

confidence: 88%

Sulforaphane prevents right ventricular injury and reduces pulmonary vascular remodeling in pulmonary arterial hypertension

Kang

Zhang

Huang

et al. 2020

American Journal of Physiology-Heart and Circulatory Physiology

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Right ventricular (RV) dysfunction is the main determinant of mortality in patients with pulmonary arterial hypertension (PAH) and while inflammation is pathogenic in PAH, there is limited information on the role of RV inflammation in PAH. Sulforaphane (SFN), a potent Nrf2 activator, has significant anti-inflammatory effects and facilitates cardiac protection in preclinical diabetic models. Therefore, we hypothesized that SFN might play a comparable role in reducing RV and pulmonary inflammation and injury in a murine PAH model. We induced PAH using SU5416 and 10% hypoxia (SuHx) for 4 wk in male mice randomized to SFN at a daily dose of 0.5 mg/kg 5 days per week for 4 wk or to vehicle control. Transthoracic echocardiography was performed to characterize chamber-specific ventricular function during PAH induction. At 4 wk, we measured RV pressure and relevant measures of histology and protein and gene expression. SuHx induced progressive RV, but not LV, diastolic and systolic dysfunction, and RV and pulmonary remodeling, fibrosis, and inflammation. SFN prevented SuHx-induced RV dysfunction and remodeling, reduced RV inflammation and fibrosis, upregulated Nrf2 expression and its downstream gene NQO1, and reduced the inflammatory mediator leucine-rich repeat and pyrin domain-containing 3 (NLRP3). SFN also reduced SuHx-induced pulmonary vascular remodeling, inflammation, and fibrosis. SFN alone had no effect on the heart or lungs. Thus, SuHx-induced RV and pulmonary dysfunction, inflammation, and fibrosis can be attenuated or prevented by SFN, supporting the rationale for further studies to investigate SFN and the role of Nrf2 and NLRP3 pathways in preclinical and clinical PAH studies. NEW & NOTEWORTHY Pulmonary arterial hypertension (PAH) in this murine model (SU5416 + hypoxia) is associated with early changes in right ventricular (RV) diastolic and systolic function. RV and lung injury in the SU5416 + hypoxia model are associated with markers for fibrosis, inflammation, and oxidative stress. Sulforaphane (SFN) alone for 4 wk has no effect on the murine heart or lungs. Sulforaphane (SFN) attenuates or prevents the RV and lung injury in the SUF5416 + hypoxia model of PAH, suggesting that Nrf2 may be a candidate target for strategies to prevent or reverse PAH.

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Section: Discussionsupporting

confidence: 88%

Sulforaphane prevents right ventricular injury and reduces pulmonary vascular remodeling in pulmonary arterial hypertension

Kang

Zhang

Huang

et al. 2020

American Journal of Physiology-Heart and Circulatory Physiology

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“…In a study of keloid pathogenesis, increased Col production, cell proliferation, and migration of keloid fibroblasts were demonstrated to be suppressed by STAT3 short interfering (si)RNA (Lim et al, 2006). An in vivo and in vitro study of cardiac hypertrophy also showed that during induction of cardiac hypertrophy, treatment of fibroblasts with specific STAT3 inhibitors or STAT3 siRNA resulted in downregulation of IL-6-induced STAT3 phosphorylation and Col type 1 and type 3 gene expressions in cardiac fibroblasts (Chatterjee et al, 2017). In the present study, treatment with an anti-IL-6 antibody to neutralize exogenous IL-6 reduced the pSTAT3/STAT3 ratio (Figure 5b).…”

Section: Suppression Of the Il-6-stat3 Signaling Pathway To Prevent Digosupporting

confidence: 74%

Role of IL‐6 and STAT3 signaling in dihydropyridine‐induced gingival overgrowth fibroblasts

Huang

et al. 2020

Oral Diseases

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Hypertension is a complex disorder with high prevalence rates worldwide. Many patients take dihydropyridines, such as nifedipine, amlodipine, nicardipine, and felodipine, to control their blood pressure. Patients with dihydropyridine-induced gingival overgrowth (DIGO) are frequently found in periodontal clinic (Figure 1).Several proinflammatory cytokines secreted into the gingival crevicular fluid (GCF), including interleukin (IL)-1β, tumor necrosis factor-α, IL-6, and IL-8, can induce periodontal tissue destruction (Ruhl et al., 2004). IL-1 and IL-6 are the most active proinflammatory cytokines involved in inflammatory diseases such as periodontitis (Cardoso et al., 2018). As a principal mediator of inflammatory responses, IL-1β can be monitored as a standard biomarker to predict the prognosis when treating chronic periodontitis (Lu & Chei, 2005). IL-6 is a multifunctional cytokine mainly produced by lymphocytes, monocytes, and fibroblasts. Elevated IL-6 levels in the blood or biological fluids were reported to be associated with immunopathologies such as tissue injury, allergies, and some inflammatory diseases (Hirano et al., 1990;Young et al., 2014).Moreover, IL-6 was demonstrated to play a major role in collagen

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“…In normal physiological states, collagen deposition and inflammatory response of heart tissue is devastatingly low, but it is significantly expanded and contributes to Ann Transl Med 2022 | https://dx.doi.org/10.21037/atm-21-6667 further damage in disease states, such as MI, cardiac hypertrophy, and heart failure (32,33). Thus, evaluation of histopathological changes in the cardiac tissue using Masson and H&E staining is necessary.…”

Section: Discussionmentioning

confidence: 99%

Asiaticoside alleviates cardiomyocyte apoptosis and oxidative stress in myocardial ischemia/reperfusion injury via activating the PI3K-AKT-GSK3β pathway in vivo and in vitro

Zeng¹,

Yu²,

Liu³

et al. 2022

Ann Transl Med

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Background: Myocardial ischemia/reperfusion (MI/R) is one of the most important links in myocardial injury, causing damage to cardiac tissues including cell apoptosis, oxidative stress, and other serious consequences. Asiaticoside (AS), a new compound synthesized from genistein, is cardioprotective. This paper presents new evidence for the protective role of AS against MI/R injury in vitro and in vivo. Methods: First, BALB/c mice underwent surgical ligation of the left anterior descending (LAD) artery to establish an MI/R animal model, and HL-1 cells were subjected to oxygen-glucose deprivation/ reperfusion (OGD/R) to establish an in vitro model. Myocardial infarct size was examined by triphenyl tetrazolium chloride (TTC) staining, histopathological changes detected in heart tissues were observed using hematoxylin and eosin (H&E) and Masson staining, heart tissue apoptosis was assessed by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. Enzyme-linked immunosorbent assay (ELISA) kits were used to analyze cardiac troponin I (CTnI), creatine kinase-muscle and brain (CK-MB), lactate dehydrogenase (LDH), superoxide dismutase (SOD), malondialdehyde (MDA), and reduced glutathione (GSH). Cell viability was evaluated using Cell Counting Kit-8 (CCK-8) and live/dead assay. Cell apoptosis, reactive oxygen species (ROS), mitochondrial membrane potential, and mitochondrial superoxide were detected by flow cytometry and fluorescence microscopy. Both the protein expression in myocardial tissues and cardiomyocytes were examined by western blot. Results: In the in vivo MI/R experiments，pretreatment of AS reduced myocardial infarct size, decrease leakage of myocardial enzyme, suppressed myocardial apoptosis, myocardial collagen deposition, and oxidative stress. In the in vitro OGD/R experiments, HL-1 cells pretreated with AS had increased cell viability, decreased apoptosis rates and depolarization of mitochondrial membrane potential, and attenuated intracellular ROS and mitochondrial superoxide. Moreover, AS downregulated the expression of apoptotic protein, and promoted phosphorylation of PI3K, AKT, and GSK3β, which was reversed by PI3K inhibitor LY294002. Conclusions: The AS compound protects against MI/R injury by attenuating oxidative stress and apoptosis via activating the PI3K/AKT/GSK3β pathway in vivo and vitro.

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Connective tissue growth factor dependent collagen gene expression induced by MAS agonist AR234960 in human cardiac fibroblasts

Cited by 6 publications

References 38 publications

Sulforaphane prevents right ventricular injury and reduces pulmonary vascular remodeling in pulmonary arterial hypertension

Sulforaphane prevents right ventricular injury and reduces pulmonary vascular remodeling in pulmonary arterial hypertension

Role of IL‐6 and STAT3 signaling in dihydropyridine‐induced gingival overgrowth fibroblasts

Asiaticoside alleviates cardiomyocyte apoptosis and oxidative stress in myocardial ischemia/reperfusion injury via activating the PI3K-AKT-GSK3β pathway in vivo and in vitro

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