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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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| KeyWord:Chinese medicine, mitophagy, ischemia-reperfusion injury, Parkin, ubiquitin |
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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 high dose 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 significantly 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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