Zhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences · 2026
[Protective effect of the endoplasmic reticulum stress inhibitor 4-phenylbutyric acid against myocardial injury in septic mice].
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Xiong Wei, Dai Jinwei, Xu Wenye, Jin Rui, Chen Yiting, Zhang Lina, Qian Zhaoxin
Аннотация
OBJECTIVES: Endoplasmic reticulum stress (ERS) is an important pathophysiological mechanism involved in the development and progression of sepsis-related myocardial injury (SRMI). This study aims to investigate the protective effect of the ERS inhibitor 4‑phenylbutyric acid (4PBA) against myocardial injury in lipopolysaccharide (LPS)‑induced SRMI.
METHODS: An SRMI mouse model was established by intraperitoneal injection of LPS in male C57BL/6J mice. In experiment 1, mice were randomly assigned to 5 groups (n=6 per group): Control, LPS 6 h, LPS 12 h, LPS 24 h, and LPS 48 h groups. In experiment 2, mice were randomly assigned to 4 groups (n=6 per group): Control, LPS, tunicamycin (TM), and TM+LPS groups. In experiment 3, mice were randomly assigned to 4 groups (n=6 per group): Control, LPS, 4PBA, and 4PBA+LPS groups. In experiment 4, mice were randomly assigned to 4 groups (n=8 per group): LPS, TM, TM+LPS, and 4PBA+LPS groups. TM (0.5 mg/kg) was administered intraperitoneally 6 h before LPS injection, and 4PBA (10 mg/kg) was administered 6 h before and 6 h after LPS injection. Cardiac function was evaluated by echocardiography. Plasma cardiac troponin I (cTnI) and creatine kinase-MB (CK-MB) levels and cardiac tissue interleukin-1β (IL-1β) levels were measured by enzyme-linked immunosorbent assay (ELISA). Histopathological changes in myocardial tissue were examined using hematoxylin-eosin (HE) staining. Western blotting was performed to determine the expression of ERS-related proteins, including inositol-requiring enzyme 1α (IRE1α), phosphorylated protein kinase R-like endoplasmic reticulum kinase (p-PERK), cleaved-activating transcription factor 6 (cleaved-ATF6), spliced X-box binding protein 1 (XBP1s), CCAAT enhancer binding protein-homologous protein (CHOP), and glucose-regulated protein 78 (GRP78), as well as the inflammatory factor tumor necrosis factor-α (TNF-α), in cardiac tissue. An in vitro sepsis model was established by treating HL-1 mouse cardiomyocytes with LPS. Cardiomyocyte apoptosis and mitochondrial membrane potential (ΔΨm) were evaluated using terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) and JC-1 mitochondrial membrane potential assays, respectively.
RESULTS: Compared with the control group, left ventricular ejection fraction (EF) and fractional shortening (FS) in the LPS 6 h, LPS 12 h, LPS 24 h, and LPS 48 h groups initially decreased and subsequently recovered over time, whereas plasma cTnI and CK-MB levels and myocardial IL-1β levels initially increased and subsequently decreased; these differences were statistically significant (all P<0.05). The expression levels of the ERS-related proteins IRE1α, XBP1s, p-PERK, CHOP, cleaved-ATF6, and GRP78 in cardiac tissues were significantly increased (all P<0.05). Marked myocardial edema, myofibrillar disruption, and loss of vascular spaces were observed. Compared with the LPS group, the 4PBA+LPS group showed significantly increased EF and FS, significantly decreased plasma cTnI and CK-MB levels and myocardial IL-1β level, and significantly reduced expression of ERS-related proteins and the inflammatory factor TNF-α in cardiac tissues (all P<0.05). The 5-day survival rate of mice showed an increasing trend, accompanied by marked amelioration of myocardial histopathological injury. The TM+LPS group showed changes in the opposite direction to those observed in the 4PBA+LPS group. In the LPS-treated HL-1 cardiomyocyte model, mitochondrial membrane potential was significantly improved in the 4PBA+LPS group compared with the LPS group (P<0.05), while the proportion of TUNEL-positive cells was significantly reduced (P<0.05).
CONCLUSIONS: Activation of ERS aggravates LPS-induced SRMI, whereas 4PBA attenuates excessive ERS activation, alleviates the inflammatory response, reduces cardiomyocyte apoptosis, improves cardiac function, and decreases mortality. Targeting ERS may represent a potential therapeutic strategy for sepsis-related myocardial injury.
METHODS: An SRMI mouse model was established by intraperitoneal injection of LPS in male C57BL/6J mice. In experiment 1, mice were randomly assigned to 5 groups (n=6 per group): Control, LPS 6 h, LPS 12 h, LPS 24 h, and LPS 48 h groups. In experiment 2, mice were randomly assigned to 4 groups (n=6 per group): Control, LPS, tunicamycin (TM), and TM+LPS groups. In experiment 3, mice were randomly assigned to 4 groups (n=6 per group): Control, LPS, 4PBA, and 4PBA+LPS groups. In experiment 4, mice were randomly assigned to 4 groups (n=8 per group): LPS, TM, TM+LPS, and 4PBA+LPS groups. TM (0.5 mg/kg) was administered intraperitoneally 6 h before LPS injection, and 4PBA (10 mg/kg) was administered 6 h before and 6 h after LPS injection. Cardiac function was evaluated by echocardiography. Plasma cardiac troponin I (cTnI) and creatine kinase-MB (CK-MB) levels and cardiac tissue interleukin-1β (IL-1β) levels were measured by enzyme-linked immunosorbent assay (ELISA). Histopathological changes in myocardial tissue were examined using hematoxylin-eosin (HE) staining. Western blotting was performed to determine the expression of ERS-related proteins, including inositol-requiring enzyme 1α (IRE1α), phosphorylated protein kinase R-like endoplasmic reticulum kinase (p-PERK), cleaved-activating transcription factor 6 (cleaved-ATF6), spliced X-box binding protein 1 (XBP1s), CCAAT enhancer binding protein-homologous protein (CHOP), and glucose-regulated protein 78 (GRP78), as well as the inflammatory factor tumor necrosis factor-α (TNF-α), in cardiac tissue. An in vitro sepsis model was established by treating HL-1 mouse cardiomyocytes with LPS. Cardiomyocyte apoptosis and mitochondrial membrane potential (ΔΨm) were evaluated using terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) and JC-1 mitochondrial membrane potential assays, respectively.
RESULTS: Compared with the control group, left ventricular ejection fraction (EF) and fractional shortening (FS) in the LPS 6 h, LPS 12 h, LPS 24 h, and LPS 48 h groups initially decreased and subsequently recovered over time, whereas plasma cTnI and CK-MB levels and myocardial IL-1β levels initially increased and subsequently decreased; these differences were statistically significant (all P<0.05). The expression levels of the ERS-related proteins IRE1α, XBP1s, p-PERK, CHOP, cleaved-ATF6, and GRP78 in cardiac tissues were significantly increased (all P<0.05). Marked myocardial edema, myofibrillar disruption, and loss of vascular spaces were observed. Compared with the LPS group, the 4PBA+LPS group showed significantly increased EF and FS, significantly decreased plasma cTnI and CK-MB levels and myocardial IL-1β level, and significantly reduced expression of ERS-related proteins and the inflammatory factor TNF-α in cardiac tissues (all P<0.05). The 5-day survival rate of mice showed an increasing trend, accompanied by marked amelioration of myocardial histopathological injury. The TM+LPS group showed changes in the opposite direction to those observed in the 4PBA+LPS group. In the LPS-treated HL-1 cardiomyocyte model, mitochondrial membrane potential was significantly improved in the 4PBA+LPS group compared with the LPS group (P<0.05), while the proportion of TUNEL-positive cells was significantly reduced (P<0.05).
CONCLUSIONS: Activation of ERS aggravates LPS-induced SRMI, whereas 4PBA attenuates excessive ERS activation, alleviates the inflammatory response, reduces cardiomyocyte apoptosis, improves cardiac function, and decreases mortality. Targeting ERS may represent a potential therapeutic strategy for sepsis-related myocardial injury.