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. 2017 Apr 20;12(4):e0176071.
doi: 10.1371/journal.pone.0176071. eCollection 2017.

Tauroursodeoxycholic acid (TUDCA) attenuates pressure overload-induced cardiac remodeling by reducing endoplasmic reticulum stress

Shilpa Rani  1 , Pradeep Kumar Sreenivasaiah  1 , Jin Ock Kim  1 , Mi Young Lee  1 , Wan Seok Kang  2 , Yong Sook Kim  2 , Youngkeun Ahn  2 , Woo Jin Park  1 , Chunghee Cho  1 , Do Han Kim  1
Affiliations

Tauroursodeoxycholic acid (TUDCA) attenuates pressure overload-induced cardiac remodeling by reducing endoplasmic reticulum stress

Shilpa Rani et al. PLoS One. .

Abstract

Pressure overload in the heart induces pathological hypertrophy and is associated with cardiac dysfunction. Apoptosis and fibrosis signaling initiated by the endoplasmic reticulum stress (ERS) is known to contribute to these maladaptive effects. The aim of this study was to investigate whether reduction of ERS by a known chemical chaperone, tauroursodeoxycholic acid (TUDCA) can attenuate pressure overload-induced cardiac remodeling in a mouse model of transverse aortic constriction (TAC). Oral administration of TUDCA at a dose of 300 mg/kg body weight (BW) in the TUDCA-TAC group reduced ERS markers (GRP78, p-PERK, and p-eIf2α), compared to the Vehicle (Veh)-TAC group. TUDCA administration, for 4 weeks after TAC significantly reduced cardiac hypertrophy as shown by the reduced heart weight (HW) to BW ratio, and expression of hypertrophic marker genes (ANF, BNP, and α-SKA). Masson's trichrome staining showed that myocardial fibrosis and collagen deposition were also significantly reduced in the TUDCA-TAC group. We also found that TUDCA significantly decreased expression of TGF-β signaling proteins and collagen isoforms. TUDCA administration also reduced cardiac apoptosis and the related proteins in the TUDCA-TAC group. Microarray analysis followed by gene ontology (GO) and pathway analysis demonstrated that extracellular matrix genes responsible for hypertrophy and fibrosis, and mitochondrial genes responsible for apoptosis and fatty acid metabolism were significantly altered in the Veh-TAC group, but the alterations were normalized in the TUDCA-TAC group, suggesting potential of TUDCA in treatment of heart diseases related to pressure-overload.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Tauroursodeoxycholic acid (TUDCA) attenuated endoplasmic reticulum stress (ERS) responses in transverse aortic constriction (TAC)-induced hypertrophic hearts.
(A) Expression levels of the chaperone proteins GRP78, and GRP94 and the ERS signaling pathway proteins p-PERK and p-eIF2α were significantly increased at 4 weeks after TAC. The western blotting results of whole heart homogenates were obtained from sham- and TAC-operated mice administered vehicle and TUDCA (300 mg kg−1 day−1). (B–E) Relative expression levels of the ERS signaling pathway proteins GRP78, GRP94, p-PERK and p-eIF2α are shown. All data are shown as mean ± SE (* P < 0.05, ** P < 0.01, n = 3).
Fig 2
Fig 2. Tauroursodeoxycholic acid (TUDCA) administration reduced hypertrophy in transverse aortic constriction (TAC)-induced hypertrophic hearts.
(A) Representative images of whole-heart cross sections obtained by microscopic analysis (hematoxylin-eosin stain) (scale bar = 2 mm). (B, C) Ratios of heart weight (HW)/ body weight (BW) and HW to tibial length as a result of following 4 week TAC and TUDCA administration (n = 5–9). (D–F) Transcription levels of ANF, BNP and α-SKA were evaluated by quantitative reverse transcription-polymerase chain reaction using hearts of the sham- and TAC-operated mice after administration of Veh or TUDCA. All data are shown as mean ± SE (* P < 0.05, ** P < 0.01, n = 3).
Fig 3
Fig 3. Tauroursodeoxycholic acid (TUDCA) administration reduced the number of apoptotic cells in transverse aortic constriction (TAC)-induced hypertrophic hearts.
(A) Protein expression of the pro-apoptotic genes CHOP and cleaved caspase 3 after 4 weeks of TUDCA administration. (B, C) Relative expression of the pro-apoptotic genes CHOP and cleaved caspase 3 (n = 3). (D) A TUNEL assay was performed using paraffin-embedded heart tissues (scale bar = 50 μm). (E) Quantitative representation of the percentage of TUNEL-positive cardiomyocytes. Only nuclei that were purplish red were scored. The percentage of TUNEL-positive cells was calculated as the ratio of TUNEL-positive to DAPI-stained nuclei in the section. Three to five fields were selected randomly for each heart section, and quantitated by ImageJ (n = 3–6). All data are shown as mean ± SE (* P < 0.05, **P < 0.01).
Fig 4
Fig 4. Tauroursodeoxycholic acid (TUDCA) alleviated cardiac fibrosis in transverse aortic constriction (TAC)-induced hypertrophic hearts.
(A) Trichrome staining was performed on histological heart sections, as described in Materials and Methods. (B) Quantitative representations of the percentage of fibrotic areas are shown. Fibrotic areas were quantified in histological sections using ImageJ. The percentage of fibrosis was determined from 4–5 images per heart focusing on both interstitial and perivascular regions, and calculated as the ratio of fibrosis to the total area of the cross section. (scale bar = 200 μm) (n = 3–5). (C) Western blot results of transforming growth factor (TGF)-β1 and Smad proteins in the whole-heart homogenates of TAC mice treated with Veh or TUDCA for 4 weeks are shown. (D, E) Relative expression levels of TGF-β1 and p-Smad proteins are shown. All data are shown as mean ± SE. (* P < 0.05, **P < 0.01).
Fig 5
Fig 5. Tauroursodeoxycholic acid (TUDCA) alleviated TAC-induced cardiac fibrosis.
(A–E) Transcripts of pro-collagens, TGF-β1, TGF-β2, CTGF, and MMP9 were evaluated by real-time polymerase chain reaction using hearts of the sham- and TAC-operated mice after administration of Veh or TUDCA for 4 weeks. All data are shown as mean ± SE. (* P < 0.05, **P < 0.01, n = 3).
Fig 6
Fig 6. Tauroursodeoxycholic acid (TUDCA) normalized altered gene expression in a pressure overload-induced hypertrophy.
The number of significantly reduced DEGs involved in the Gene Ontology (GO) (biological process) or Ingenuity toxicity pathways in the TUDCA-TAC group, compared to the Veh-TAC group. Significantly enriched GO pathways (P < 0.05) with at least five DEGs for Veh-TAC or TUDCA-TAC in comparison to control group (Veh-Sham or TUDCA-Sham) are shown. GO analysis was performed using DAVID bioinformatics resources 6.7 (https://david.ncifcrf.gov/)). The Ingenuity toxicity analysis of microarray data was performed by Ingenuity Pathway Analysis (IPA) software. Color intensity represents degree of enrichment (-log10 [p-value]) and the number represents the number of genes.
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This work was supported by GIST Research Institute (GRI) grant funded by GIST in 2017, and the NRF grant funded by the Korean Ministry of Science, ICT & Future Planning (NRF-2013M3A9A7046297).

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