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Mechanism of Qili Qiangxin Capsule for Heart Failure Based on miR133a-Endoplasmic Reticulum Stress

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Abstract

Objective

To investigate the pharmacological mechanism of Qili Qiangxin Capsule (QLQX) improvement of heart failure (HF) based on miR133a-endoplasmic reticulum stress (ERS) pathway.

Methods

A left coronary artery ligation-induced HF after myocardial infarction model was used in this study. Rats were randomly assigned to the sham group, the model group, the QLQX group [0.32 g/(kg·d)], and the captopril group [2.25 mg/(kg·d)], 15 rats per group, followed by 4 weeks of medication. Cardiac function such as left ventricular ejection fraction (EF), fractional shortening (FS), left ventricular systolic pressure (LVSP), left ventricular end diastolic pressure (LVEDP), the maximal rate of increase of left ventricular pressure (+dp/dt max), and the maximal rate of decrease of left ventricular pressure (−dp/dt max) were monitored by echocardiography and hemodynamics. Hematoxylin and eosin (HE) and Masson stainings were used to visualize pathological changes in myocardial tissue. The mRNA expression of miR133a, glucose-regulated protein78 (GRP78), inositol-requiring enzyme 1 (IRE1), activating transcription factor 6 (ATF6), X-box binding protein1 (XBP1), C/EBP homologous protein (CHOP) and Caspase 12 were detected by RT-PCR. The protein expression of GRP78, p-IRE1/IRE1 ratio, cleaved-ATF6, XBP1-s (the spliced form of XBP1), CHOP and Caspase 12 were detected by Western blot. TdT-mediated dUTP nick-end labeling (TUNEL) staining was used to detect the rate of apoptosis.

Results

QLQX significantly improved cardiac function as evidenced by increased EF, FS, LVSP, +dp/dt max, −dp/dt max, and decreased LVEDP (P<0.05, P<0.01). HE staining showed that QLQX ameliorated cardiac pathologic damage to some extent. Masson staining indicated that QLQX significantly reduced collagen volume fraction in myocardial tissue (P<0.01). Results from RT-PCR and Western blot showed that QLQX significantly increased the expression of miR133a and inhibited the mRNA expressions of GRP78, IRE1, ATF6 and XBP1, as well as decreased the protein expressions of GRP78, cleaved-ATF6 and XBP1-s and decreased p-IRE1/IRE1 ratio (P<0.05, P<0.01). Further studies showed that QLQX significantly reduced the expression of CHOP and Caspase12, resulting in a significant reduction in apoptosis rate (P<0.05, P<0.01).

Conclusion

The pharmacological mechanism of QLQX in improving HF is partly attributed to its regulatory effect on the miR133a-IRE1/XBP1 pathway.

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Data Availability

The data used to support the findings of this study are available from the corresponding author upon request.

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Authors and Affiliations

  1. Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Beijing, 100700, China

    Xiao-di Ji, Ding Yang, Xi-yuan Cui, Li-xia Lou, Bo Nie, Jiu-li Zhao, Ming-jing Zhao & Ai-ming Wu

  2. Department of Traditional Chinese Medicine, Fuwai Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100037, China

    Xiao-di Ji

Authors
  1. Xiao-di Ji
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Contributions

Wu AM designed the general study and revised the manuscript. Zhao MJ guided the manuscript writing ideas as well as provided important advice on the experimental design.

Corresponding author

Correspondence to Ai-ming Wu.

Ethics declarations

The authors declare that they have no conflicts of interest.

Additional information

Supported by 2022 Science and Technology Innovation Project of Dongzhimen Hospital, Beijing University of Chinese Medicine (No. DZMKJCX-2022-008)

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Ji, Xd., Yang, D., Cui, Xy. et al. Mechanism of Qili Qiangxin Capsule for Heart Failure Based on miR133a-Endoplasmic Reticulum Stress. Chin. J. Integr. Med. 30, 398–407 (2024). https://doi.org/10.1007/s11655-024-3654-3

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  • DOI: https://doi.org/10.1007/s11655-024-3654-3

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