4-Phenylbutyric acid prevent cytotoxicity induced by thapsigargin in rat cardiac fibroblast

Humeres, Claudio; Montenegro, José Luis Cadena; Varela, Marcelo; Ayala, Pedro; Vivar, Raúl; Letelier, A; Olmedo, Ivonne; Catalán, Mabel; Rivas, Claudia Paz Iriarte; Baeza, P.; Muñoz, Claudia; Garcı́a, Lorena; Lavandero, Sergio; Díaz‐Araya, Guillermo

doi:10.1016/j.tiv.2014.07.013

Cited by 19 publications

(13 citation statements)

References 41 publications

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“…Noted by this group was an increase in the acetylation of histone H4 as well as cAMP, suggesting that 4-PBA may act as a HDACi generating these effects (Rishikof et al, 2004). Another recent study has discovered further evidence of 4-PBA inhibiting collagen synthesis by suggesting that 4-PBA decreases procollagen levels in cardiac fibroblasts (Humeres et al, 2014). In a hyperglycemic model of ER stress both pro-collagen 1 and collagen 1 levels are significantly reduced in gingival fibroblasts after 4-PBA administration .…”

Section: The Effects Of 4-pba On Neurological Diseases and Models Of mentioning

confidence: 74%

The therapeutic effects of 4-phenylbutyric acid in maintaining proteostasis

Kolb

Ayaub

Zhou

et al. 2015

The International Journal of Biochemistry & Cell Biology

209

172

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Section: The Effects Of 4-pba On Neurological Diseases and Models Of mentioning

confidence: 74%

The therapeutic effects of 4-phenylbutyric acid in maintaining proteostasis

Kolb

Ayaub

Zhou

et al. 2015

The International Journal of Biochemistry & Cell Biology

209

172

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“…For example, in cultured neonatal rat cardiomyocytes, application of ER stress inducer thapsigargin (TG) produced cellular hypertophy in a dose- and time-dependent manner [7]. TG also triggered the UPR and accumulation of intracellular procollagen in cultured rat cardiac fibroblasts [21]. Furthermore, accumulating in-vivo data from the pressure overload model implicates ER stress as a central player in the development of cardiac hypertrophy [22–24].…”

Section: Discussionmentioning

confidence: 99%

4-PBA prevents pressure overload-induced myocardial hypertrophy and interstitial fibrosis by attenuating endoplasmic reticulum stress

Luo

Chen

Wang

2015

Chemico-Biological Interactions

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Our previous study indicated that attenuation of endoplasmic reticulum (ER) stress by administration of 4-phenylbutyric acid (4-PBA) could prevent cardiac rupture and remodeling in a mouse model of myocardial infarction (MI). However, whether 4-PBA is protective in hypertrophic heart disease is unclear. Thus, we tested the therapeutic effect of 4-PBA on pressure-overload induced myocardial hypertrophy. Transverse aortic constriction (TAC) was used to create myocardial hypertrophy in C57BL/6 male mice for 4 weeks. Immediately after surgery, the mice were administrated either 4-PBA (20 mg/kg/day) or 0.9% NaCl by intraperitoneal injection. At the end of 4 weeks, the mice underwent high-resolution echocardiographic imaging. Our results showed that both the left ventricular posterior wall thickness at end systole (LVPWs) and diastole (LVPWd) were increased in the TAC group, compared to control. 4-PBA administration attenuated hypertrophy and decreased the heart weight over body weight ratio. Masson’s trichrome staining showed that myocardial interstitial fibrosis and collagen deposition were also decreased by 4-PBA. We next detected the ER stress response in the heart tissues of TAC mice in different time points. Western blotting showed that the expression of ER stress marker, GRP78, CHOP and phosphor-PERK, were persistently increased 4 weeks after TAC. The treatment of 4-PBA inhibited the expression of ER stress markers. We also demonstrated that the 4-PBA at 20 mg/kg/day had no effect on histone 3 deacetylation inhibition, while attenuating ER stress and TAC-induced hypertrophy. These findings suggest that 4-PBA may be a therapeutic strategy to consider in preventing pressure-overload induced myocardial hypertrophy and interstitial fibrosis by selectively attenuating ER stress.

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“…Experimentally, ER Ca 2+ depletion and a resulting UPR can be achieved by use of the specific sarco/endoplasmic reticulum Ca 2+ -ATPase (SERCA) inhibitor thapsigargin (Tg; for chemical structure see Additional file 1: Figure S1A) -a classical tool to study ER stress and UPR biology. Tg produces sustained and unmitigated ER stress in mammalian cells, leading to UPR-induced apoptosis [7][8][9][10][11][12][13]. Besides its use as an experimental tool, Tg is the mother compound of prodrugs designed for use in targeted cancer therapy [14][15][16].…”

Section: Introductionmentioning

confidence: 99%

Cell death induced by the ER stressor thapsigargin involves death receptor 5, a non-autophagic function of MAP1LC3B, and distinct contributions from unfolded protein response components

et al. 2020

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Background: Cell death triggered by unmitigated endoplasmic reticulum (ER) stress plays an important role in physiology and disease, but the death-inducing signaling mechanisms are incompletely understood. To gain more insight into these mechanisms, the ER stressor thapsigargin (Tg) is an instrumental experimental tool. Additionally, Tg forms the basis for analog prodrugs designed for cell killing in targeted cancer therapy. Tg induces apoptosis via the unfolded protein response (UPR), but how apoptosis is initiated, and how individual effects of the various UPR components are integrated, is unclear. Furthermore, the role of autophagy and autophagy-related (ATG) proteins remains elusive.Methods: To systematically address these key questions, we analyzed the effects of Tg and therapeutically relevant Tg analogs in two human cancer cell lines of different origin (LNCaP prostate-and HCT116 colon cancer cells), using RNAi and inhibitory drugs to target death receptors, UPR components and ATG proteins, in combination with measurements of cell death by fluorescence imaging and propidium iodide staining, as well as real-time RT-PCR and western blotting to monitor caspase activity, expression of ATG proteins, UPR components, and downstream ER stress signaling.Results: In both cell lines, Tg-induced cell death depended on death receptor 5 and caspase-8. Optimal cytotoxicity involved a non-autophagic function of MAP1LC3B upstream of procaspase-8 cleavage. PERK, ATF4 and CHOP were required for Tg-induced cell death, but surprisingly acted in parallel rather than as a linear pathway; ATF4 and CHOP were independently required for Tg-mediated upregulation of death receptor 5 and MAP1LC3B proteins, whereas PERK acted via other pathways. Interestingly, IRE1 contributed to Tg-induced cell death in a cell typespecific manner. This was linked to an XBP1-dependent activation of c-Jun N-terminal kinase, which was proapoptotic in LNCaP but not HCT116 cells. Molecular requirements for cell death induction by therapy-relevant Tg analogs were identical to those observed with Tg. Conclusions: Together, our results provide a new, integrated understanding of UPR signaling mechanisms and downstream mediators that induce cell death upon Tg-triggered, unmitigated ER stress.

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4-Phenylbutyric acid prevent cytotoxicity induced by thapsigargin in rat cardiac fibroblast

Cited by 19 publications

References 41 publications

The therapeutic effects of 4-phenylbutyric acid in maintaining proteostasis

The therapeutic effects of 4-phenylbutyric acid in maintaining proteostasis

4-PBA prevents pressure overload-induced myocardial hypertrophy and interstitial fibrosis by attenuating endoplasmic reticulum stress

Cell death induced by the ER stressor thapsigargin involves death receptor 5, a non-autophagic function of MAP1LC3B, and distinct contributions from unfolded protein response components

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