Chemical chaperone 4-phenylbutyric acid protects H9c2 cardiomyocytes from ischemia/reperfusion injury by attenuating endoplasmic reticulum stress-induced apoptosis

Jian,Lian; Lu,Yuan; Lu,Shan; Lu,Chengzhi

doi:10.3892/mmr.2016.5063

Chemical chaperone 4-phenylbutyric acid protects H9c2 cardiomyocytes from ischemia/reperfusion injury by attenuating endoplasmic reticulum stress-induced apoptosis

Authors:
- Lian Jian
- Yuan Lu
- Shan Lu
- Chengzhi Lu
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Affiliations: Cardiovascular Department, Tianjin First Central Hospital, Tianjin 300192, P.R. China, Radiology Department, Tianjin Medical University Metabolic Diseases Hospital, Tianjin 300000, P.R. China
Published online on: March 30, 2016 https://doi.org/10.3892/mmr.2016.5063
Pages: 4386-4392

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Abstract

Myocardial ischemia/reperfusion (I/R) is a potential contributor to high rates of mortality in several cardiovascular diseases. I/R initiates the unfolded protein response and endoplasmic reticulum (ER) stress, which may lead to apoptotic pathways and exaggerate I/R injury. 4‑phenylbutyric acid (4‑PBA), a low molecular weight, terminal aromatic substituted fatty acid, has been reported to function as an ER chaperone. The aim of the present study was to investigate whether 4‑PBA is able to reduce ER stress‑induced apoptosis and prevent cardiomyocyte damage during the process of I/R in vitro. Accordingly, the rat cardiomyocyte line, H9c2, was treated with hypoxia/reoxygenation as an I/R model in vitro. Myocardium apoptosis was determined with TUNEL staining. The expression of ER stress‑related proteins were examined by western blotting. The resulting data showed that I/R activates the ER stress proteins, glucose‑regulated protein 78, activating transcription factor 6 and protein kinase RNA‑like endoplasmic reticulum kinase, which were all reduced by pretreatment with 4‑PBA. In addition, pretreatment with 4‑PBA significantly inhibited the expression levels of pro‑apoptotic proteins, C/EBP homologous protein, B cell lymphoma (Bcl‑2)‑associated X protein and phosphorylated c‑Jun N‑terminal kinase, and enhanced the expression of the anti‑apoptotic protein Bcl‑2 (n=3; P<0.05). The data demonstrated that I/R initiates ER stress‑associated apoptotic pathways, and 4‑PBA pretreatment protected the cardiomyocytes from I/R‑induced cell death. To the best of our knowledge, the present study is the first to report on the cell repair mechanism of 4‑PBA against I/R damage in cardiomyocytes based on ER stress‑associated apoptotic pathways.

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