TGF-β1 decreases CHOP expression and prevents cardiac fibroblast apoptosis induced by endoplasmic reticulum stress

Olivares-Silva, Francisco; Espitia-Corredor, Jenaro; Letelier, A; Vivar, Raúl; Parra-Flores, Pablo; Olmedo, Ivonne; Montenegro, José Luis Cadena; Pardo-Jiménez, V.; Díaz‐Araya, Guillermo

doi:10.1016/j.tiv.2020.105041

Cited by 10 publications

(12 citation statements)

References 40 publications

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“…It is well known that TGFβ1 exerts cardioprotective effects and anti-apoptotic activity in CF under simulated I/R (19). The data from the present study are in accordance with the previous observations (19,20); it was also demonstrated that TGFβ1 partly prevented OGD induced CFs death.…”

Section: Discussionsupporting

confidence: 93%

mTORC1 is a key regulator that mediates OGD‑ and TGFβ1‑induced myofibroblast transformation and chondroitin‑4‑sulfate expression in cardiac fibroblasts

Zhang

et al. 2022

Exp Ther Med

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Ischemia-reperfusion infarct-derived chondroitin sulfate proteoglycans (CSPGs) are important for sustaining denervation of the infarct. Sympathetic denervation within the heart after myocardial infarction (MI) predicts the probability of a higher risk for serious ventricular arrhythmias. Chondroitin-4-sulfate (C4S) is the predominant chondroitin sulfate component in the heart. However, the mechanisms that induce CSPG expression in fibroblasts following MI remain to be elucidated. The present study found that oxygen-glucose deprivation (OGD) and TGFβ1 stimulation induced myofibroblast transformation and C4S synthesis in vitro by using reverse transcription-quantitative PCR, western blotting and immunofluorescence. MTT assay was used to detect cell viability following OGD or OGD + TGF lotreatment. Using the PI3K inhibitor ZSTK474, the Akt inhibitor MK2206, or the mTOR inhibitor AZD8055, it was observed that OGD and TGFβ1 stimulation induced myofibroblast transformation and that C4S synthesis was mTOR-dependent, whereas the upstream canonical PI3K/Akt axis was dispensable by using western blotting and immunofluorescence. siRNA knockdown of Smad3, Raptor, or Rictor, indicated that mTORC1 was critical for promoting OGD-and TGFβ1-induced myofibroblast transformation and C4S synthesis by using western blotting and immunofluorescence. This response, may be mediated via cooperation between canonical Smad3 and mTORC1 signaling. These data suggested that inhibiting myofibroblast transformation may reduce C4S synthesis. Target mTORC1 may provide additional insight into the regeneration of sympathetic nerves and the reduction of fibrosis after MI at the cellular level. These findings may contribute to the understanding of the mechanism by which C4S overproduction in the hearts of patients with MI is associated with myocardial fibrosis.

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Section: Discussionsupporting

confidence: 93%

mTORC1 is a key regulator that mediates OGD‑ and TGFβ1‑induced myofibroblast transformation and chondroitin‑4‑sulfate expression in cardiac fibroblasts

Zhang

et al. 2022

Exp Ther Med

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“…The role of C/EBP ζ in noncardiomyocytes in fibrosis remains somewhat contradictory. Consistent with its role in cardiomyocytes, C/EBP ζ upregulation by I/R or tunicamycin can cause apoptosis of cardiac fibroblasts, thereby mitigating fibrosis [ 316 ]. However, increased C/EBP ζ levels in primary cardiac fibroblasts explored to Ang II can increase the expression of ECM proteins, as confirmed by a decrease in C/EBP ζ expression and fibrotic markers after treatment with an ER stress inhibitor [ 317 ].…”

Section: Roles Of C/ebps In the Fibrotic Processmentioning

confidence: 99%

“…For example, TGF- β 1 not only upregulates C/EBP β expression in lung fibroblasts and HSCs but also enhances C/EBP β activity by promoting its acetylation in alveolar epithelial cells [ 149 , 152 , 203 , 213 ]. In tubular epithelial cells, TGF- β 1 suppresses C/EBP β expression through the PDE/cAMP/Epac pathway to regulate mitochondria biogenesis [ 267 ], yet in cardiac fibroblasts, TGF- β 1 treatment inhibits C/EBP ζ expression [ 316 ]. Furthermore, the positive feedback loop formed by TGF- β 1 and C/EBP β in cardiac fibroblasts and by TGF- β 1 and C/EBP δ in pancreatic stellate cells may accelerate their activation [ 298 , 367 ].…”

Section: Crosstalk Between C/ebps and Classical Fibrotic Factorsmentioning

confidence: 99%

CCAAT/Enhancer-Binding Proteins in Fibrosis: Complex Roles Beyond Conventional Understanding

et al. 2022

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CCAAT/enhancer-binding proteins (C/EBPs) are a family of at least six identified transcription factors that contain a highly conserved basic leucine zipper domain and interact selectively with duplex DNA to regulate target gene expression. C/EBPs play important roles in various physiological processes, and their abnormal function can lead to various diseases. Recently, accumulating evidence has demonstrated that aberrant C/EBP expression or activity is closely associated with the onset and progression of fibrosis in several organs and tissues. During fibrosis, various C/EBPs can exert distinct functions in the same organ, while the same C/EBP can exert distinct functions in different organs. Modulating C/EBP expression or activity could regulate various molecular processes to alleviate fibrosis in multiple organs; therefore, novel C/EBPs-based therapeutic methods for treating fibrosis have attracted considerable attention. In this review, we will explore the features of C/EBPs and their critical functions in fibrosis in order to highlight new avenues for the development of novel therapies targeting C/EBPs.

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“…In CRS, the activation of ER stress in the heart and kidney could be induced by different factors, such as hemodynamic changes, hormones from the RAAS, inflammation or oxidative stress [ 346 , 347 , 348 ]. These pathophysiological mediators could directly induce ER stress in the myocardium or renal parenchyma, resulting in apoptotic cell death due to prolonged UPR activation [ 349 , 350 , 351 ] and the consequent fibrotic wound formation, all of which would eventually lead to structural and functional changes [ 348 , 352 , 353 , 354 ]. Our group has recently evaluated the effect of myocardial infarction (MI) at renal level in rats.…”

Section: Mechanisms Involved In Fibrosis Progressionmentioning

confidence: 99%

Fibrosis, the Bad Actor in Cardiorenal Syndromes: Mechanisms Involved

Delgado-Valero

Cachofeiro

Martínez‐Martínez

2021

Cells

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Cardiorenal syndrome is a term that defines the complex bidirectional nature of the interaction between cardiac and renal disease. It is well established that patients with kidney disease have higher incidence of cardiovascular comorbidities and that renal dysfunction is a significant threat to the prognosis of patients with cardiac disease. Fibrosis is a common characteristic of organ injury progression that has been proposed not only as a marker but also as an important driver of the pathophysiology of cardiorenal syndromes. Due to the relevance of fibrosis, its study might give insight into the mechanisms and targets that could potentially be modulated to prevent fibrosis development. The aim of this review was to summarize some of the pathophysiological pathways involved in the fibrotic damage seen in cardiorenal syndromes, such as inflammation, oxidative stress and endoplasmic reticulum stress, which are known to be triggers and mediators of fibrosis.

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TGF-β1 decreases CHOP expression and prevents cardiac fibroblast apoptosis induced by endoplasmic reticulum stress

Cited by 10 publications

References 40 publications

mTORC1 is a key regulator that mediates OGD‑ and TGFβ1‑induced myofibroblast transformation and chondroitin‑4‑sulfate expression in cardiac fibroblasts

mTORC1 is a key regulator that mediates OGD‑ and TGFβ1‑induced myofibroblast transformation and chondroitin‑4‑sulfate expression in cardiac fibroblasts

CCAAT/Enhancer-Binding Proteins in Fibrosis: Complex Roles Beyond Conventional Understanding

Fibrosis, the Bad Actor in Cardiorenal Syndromes: Mechanisms Involved

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