Salubrinal Alleviates Pressure Overload-Induced Cardiac Hypertrophy by Inhibiting Endoplasmic Reticulum Stress Pathway

Figures

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  Fig. 1. Salubrinal (Sal) attenuated endoplasmic reticulum stress (ERS) responses in transverse aortic constriction (TAC)-induced hypertrophic hearts (A–E) Protein expression levels of p-IRE1-α, GRP78, GRP94, and p-eIF2-α. All data represent mean ± SEM; *P < 0.05, **P < 0.01 vs. Veh SHAM, and #P < 0.05 vs. Veh TAC. (n = 3)

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  Fig. 2. Salubrinal (Sal) reduced cardiomyocyte hypertrophy (A) Immunofluorescence imaging showing cell sizes of NRVMs treated with 100 nM endothelin1 (ET1) in the presence or absence of 75 μM salubrinal (scale bar, 100 μm). (B) Fold increase in cell surface area compared to dimethyl sulfoxide (DMSO) control. All data represent mean ± SEM; *P < 0.05, **P < 0.01 vs. DMSO control and #P < 0.05, ##P < 0.01 vs. ET1. (n = 100 cells for each group)

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  Fig. 3. Salubrinal (Sal) reduced cardiac hypertrophy (A) Cross sections of hearts under different experimental conditions (scale bar, 2 mm). (B) HW/BW and (C) HW/TL ratios for the various experimental groups (n = 6–8). Salubrinal (Sal) reduced fetal gene expression in TAC induced cardiac hypertrophy. (D and E) Relative mRNA levels of ANP (NPPA), and BNP (NPPB) were evaluated using qRT-PCR (n = 5–6). (F, G) Protein expression levels of ANP and BNP (n = 3–5). All data represent mean ± SEM; *P < 0.05, **P <0.01 vs. Veh SHAM and #P < 0.05, ##P <0.01 vs. Veh TAC.

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  Fig. 4. Salubrinal (Sal) attenuated TGF-β pathway signaling molecules (A) TGF-β expression in whole heart homogenates from SHAM and TAC-induced mice treated with vehicle or salubrinal (0.5 mg·kg−1·day−1 ) for 1 week (n = 3). (B, C) Transcripts for collagen isoforms (n = 3–6) were evaluated using qRT-PCR in hearts of SHAM and TAC-induced mice after treatment with vehicle or salubrinal. All data are mean ± SEM; *P < 0.05, **P <0.01 vs. Veh SHAM, #P < 0.05, ##P <0.01 vs. Veh TAC.

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  Fig. 5. Schematic representation of the events initiated in TAC-operated mouse heart and salubrinal treated TAC-operated mouse heart The visual model shows that salubrinal treatment increases the abundance of p-eIF2α leading to attenuation of protein synthesis and reduction of cardiac hypertrophy and ER stress/UPR. The Sal TAC hearts showed a decreased p-IRE, GRP78, GRP94, and p-JNK levels.