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Tongxinluo Ameliorates Myocardial Ischemia-Reperfusion Injury Mainly via Activating Parkin-Mediated Mitophagy and Downregulating Ubiquitin-Proteasome System

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Abstract

Objective

To investigate the protective effects and mechanism of Chinese herbal compound Tongxinluo Capsule (通心络胶囊, TXL) on the Parkin-mediated mitophagy and the ubiquitin-proteasome system in a rat model of myocardial ischemia-reperfusion injury (MIRI).

Methods

Seventy adult male Sprague-Dawley rats were randomly divided into 7 groups: sham group, MIRI group, low- and high-dose TXL (0.5 and 1 g·kg-1·d-1, respectively) groups, atorvastatin (ATV) group (7.2 g·kg-1·d-1), chloroquine (CQ) group (10 g·kg-1·d-1), and highdose TXL + CQ group. After pharmacological administration for 7 days, rats underwent left anterior descending artery ligation surgery to establish the MIRI models with 50 min ischemia followed by 4 h reperfusion. Blood was taken for cardiac troponin I (cTnI) detection and hearts were harvested for infarct staining and apoptosis detection. The autophagy or mitophagy proteins and ubiquitinated proteins were detected by Western blotting.

Results

Compared with the sham group, the MIRI group exhibited a larger infarcted area (27.13%±0.01%, P<0.01), a higher apoptotic index (34.33%±2.03% vs.1.81%±0.03%, P<0.01), and higher cTnI expression (14.18±1.01 vs. 7.96±0.32, P<0.01). The mitochondrial integrity was damaged in the MIRI group, while TXL and ATV alleviated the damage of MIRI. More autophagosomes were observed in the high-dose TXL group than in the MIRI group (7.00±0.58 vs. 4.33±1.15, P<0.05). More amounts of PTEN-induced putative kinase protein 1 (PINK1) and Parkin translocated onto the mitochondria were detected in the high-dose TXL group than in the MIRI group (P<0.05). The ubiquitin response was signifificantly downregulated in the high-dose TXL group relative to the MIRI group (P<0.05). CQ administration abolished the activation of autophagy flux and the PINK1/ Parkin pathway induced by high-dose of TXL.

Conclusions

TXL ameliorates MIRI via activating Parkin-mediated mitophagy in rats. The downregulation of the ubiquitin-proteasome system is also involved.

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Authors and Affiliations

  1. Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 100029, China

    Hong-xing Yang & Peng Wang

  2. Institute of Radiation Medicine, Academy of Military Medical Sciences, Beijing, 100850, China

    Ning-ning Wang

  3. Department of Traditional Chinese Medicine, Chinese People’s Liberation Army General Hospital, Beijing, 100853, China

    Shao-dan Li & Ming-hui Yang

Authors
  1. Hong-xing Yang
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  2. Peng Wang
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  3. Ning-ning Wang
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  4. Shao-dan Li
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  5. Ming-hui Yang
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Corresponding author

Correspondence to Ming-hui Yang.

Additional information

Supported by the National Basic Research Program (973 Program) of China (No. 2012CB518601)

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Yang, Hx., Wang, P., Wang, Nn. et al. Tongxinluo Ameliorates Myocardial Ischemia-Reperfusion Injury Mainly via Activating Parkin-Mediated Mitophagy and Downregulating Ubiquitin-Proteasome System. Chin. J. Integr. Med. 27, 542–550 (2021). https://doi.org/10.1007/s11655-019-3166-8

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