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Tongmai Yangxin pill reduces myocardial no-reflow by regulating apoptosis and activating PI3K/Akt/eNOS pathway.
J Ethnopharmacol. 2020 Jun 30; 261:113069.JE

Abstract

ETHNOPHARMACOLOGICAL RELEVANCE

Tongmai Yangxin pill (TMYX) is derived from the Zhigancao decoction recorded in Shang han lun by Zhang Zhongjing during the Han dynasty and was further improved by Professor Ruan Shiyi, a cardiovascular expert at Tianjin University of Traditional Chinese Medicine. TMYX is used for the clinical treatment of chest pain, heartache, and qi-yin-deficiency coronary heart disease and can improve vascular endothelial function in patients with angina pectoris or coronary heart disease by up-regulating nitric oxide activity and then regulating vascular tension. Whether TMYX can further improve myocardial no-reflow by up-regulating NO activity and then dilating blood vessels remains unclear.

AIM OF THE STUDY

This study aimed to reveal whether TMYX can further improve myocardial NR by up-regulating NO activity and then dilating blood vessels. The mechanism underlying PI3K/Akt/eNOS pathway activation and apoptosis regulation is also explored.

MATERIALS AND METHODS

The left anterior descending coronary arteries of healthy adult male SD rats were ligated to establish a NR model. The rats were assigned to 14 groups: control, sham, NR, TMYX (4.0 g/kg), sodium nitroprusside (SNP), Tongxinluo capsule (TXL), PI3K blocker (LY), TMYX + LY, SNP + LY, TXL + LY, eNOS blocker (L-NAME), TMYX + L-NAME, SNP + L-NAME, and TXL + L-NAME groups. Cardiac function was measured through echocardiography. Thioflavin S, Evans Blue, and TTC staining were adopted to evaluate NR and ischemic areas. Cell inflammation degree and edema were assessed by hematoxylin-eosin staining. Automated biochemical analyzer and kit were used to detect the activities of myocardial oxidants, including reactive oxygen species, super oxide dismutase, malonaldehyde, and NO. The expression levels of genes and proteins in the PI3K/Akt/eNOS signaling pathway and apoptosis were detected via real-time fluorescence quantitative PCR and Western blot analysis, respectively. A microvascular tension sensor was adopted to detect coronary artery diastolic function in vitro.

RESULTS

TMYX reduced NR and ischemic areas; suppressed LV-mass; enhanced EF, FS, LVOT peak, and LVSV; and improved cardiac structure and function. Moreover, it decreased creatine kinase (CK), CK-MB, and lactic dehydrogenase activities. TMYX increased NO and super oxide dismutase activities; inhibited malonaldehyde activity; reduced muscle fiber swelling and inflammatory cell infiltration; and improved vasodilation in vitro. In the NR myocardium, TMYX stimulated myocardial PI3K activities and PI3K (Tyr458) phosphorylation and enhanced Akt activities and Akt phosphorylation at Tyr315. TMYX increased the activities of eNOS and the phosphorylation of eNOS at Ser1177 in the NR myocardium and attenuated cardiomyocyte apoptosis by increasing the expression of Bcl-2 and decreasing that of caspase-3 and Bax. All these effects of TMYX were abolished by the specific inhibitors of PI3K (LY) and eNOS (L-NAME).

CONCLUSIONS

TMYX attenuates myocardial NR after ischemia and reperfusion by activating the PI3K/Akt/eNOS pathway and regulating apoptosis, further up-regulating NO activity and relaxing coronary microvessels.

Authors+Show Affiliations

Institute of traditional Chinese medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, China. Electronic address: jbwkzchenrui@163.com.Institute of traditional Chinese medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, China. Electronic address: 13920368971@163.com.Institute of traditional Chinese medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, China. Electronic address: wangtianhua_87@126.com.Institute of traditional Chinese medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, China. Electronic address: 874511770@qq.com.Institute of traditional Chinese medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, China. Electronic address: likening1992@163.com.Institute of traditional Chinese medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, China. Electronic address: 1361623148@qq.com.Institute of traditional Chinese medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, China. Electronic address: 1002169896@qq.com.Institute of traditional Chinese medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, China. Electronic address: wangyywang@yeah.net.Institute of traditional Chinese medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, China. Electronic address: z.k.ken@263.net.Tianjin Zhongxin Pharmaceutical Group Co. Ltd. Research Institute Branch, Tianjin, 300457, China. Electronic address: gengtonggt@zx-innova.com.Tianjin Zhongxin Pharmaceutical Group Co. Ltd, Drug Marketing Co., Ltd, Tianjin, 300193, China. Electronic address: 196718330@qq.com.Institute of traditional Chinese medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, China. Electronic address: wangyi@tjutcm.edu.cn.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32619593

Citation

Chen, Rui, et al. "Tongmai Yangxin Pill Reduces Myocardial No-reflow By Regulating Apoptosis and Activating PI3K/Akt/eNOS Pathway." Journal of Ethnopharmacology, vol. 261, 2020, p. 113069.
Chen R, Chen T, Wang T, et al. Tongmai Yangxin pill reduces myocardial no-reflow by regulating apoptosis and activating PI3K/Akt/eNOS pathway. J Ethnopharmacol. 2020;261:113069.
Chen, R., Chen, T., Wang, T., Dai, X., Meng, K., Zhang, S., Jiang, D., Wang, Y., Zhou, K., Geng, T., Xu, J., & Wang, Y. (2020). Tongmai Yangxin pill reduces myocardial no-reflow by regulating apoptosis and activating PI3K/Akt/eNOS pathway. Journal of Ethnopharmacology, 261, 113069. https://doi.org/10.1016/j.jep.2020.113069
Chen R, et al. Tongmai Yangxin Pill Reduces Myocardial No-reflow By Regulating Apoptosis and Activating PI3K/Akt/eNOS Pathway. J Ethnopharmacol. 2020 Jun 30;261:113069. PubMed PMID: 32619593.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Tongmai Yangxin pill reduces myocardial no-reflow by regulating apoptosis and activating PI3K/Akt/eNOS pathway. AU - Chen,Rui, AU - Chen,Ting, AU - Wang,Tianqi, AU - Dai,Xiangdong, AU - Meng,Ke, AU - Zhang,Shuying, AU - Jiang,Di, AU - Wang,Yanyan, AU - Zhou,Kun, AU - Geng,Tong, AU - Xu,Jinpeng, AU - Wang,Yi, Y1 - 2020/06/30/ PY - 2020/02/25/received PY - 2020/05/15/revised PY - 2020/05/31/accepted PY - 2020/7/4/pubmed PY - 2020/7/4/medline PY - 2020/7/4/entrez KW - Apoptosis KW - Coronary microvessel KW - Myocardial ischemia–reperfusion no-reflow KW - PI3K/Akt/eNOS pathway KW - Tongmai yangxin pill SP - 113069 EP - 113069 JF - Journal of ethnopharmacology JO - J Ethnopharmacol VL - 261 N2 - ETHNOPHARMACOLOGICAL RELEVANCE: Tongmai Yangxin pill (TMYX) is derived from the Zhigancao decoction recorded in Shang han lun by Zhang Zhongjing during the Han dynasty and was further improved by Professor Ruan Shiyi, a cardiovascular expert at Tianjin University of Traditional Chinese Medicine. TMYX is used for the clinical treatment of chest pain, heartache, and qi-yin-deficiency coronary heart disease and can improve vascular endothelial function in patients with angina pectoris or coronary heart disease by up-regulating nitric oxide activity and then regulating vascular tension. Whether TMYX can further improve myocardial no-reflow by up-regulating NO activity and then dilating blood vessels remains unclear. AIM OF THE STUDY: This study aimed to reveal whether TMYX can further improve myocardial NR by up-regulating NO activity and then dilating blood vessels. The mechanism underlying PI3K/Akt/eNOS pathway activation and apoptosis regulation is also explored. MATERIALS AND METHODS: The left anterior descending coronary arteries of healthy adult male SD rats were ligated to establish a NR model. The rats were assigned to 14 groups: control, sham, NR, TMYX (4.0 g/kg), sodium nitroprusside (SNP), Tongxinluo capsule (TXL), PI3K blocker (LY), TMYX + LY, SNP + LY, TXL + LY, eNOS blocker (L-NAME), TMYX + L-NAME, SNP + L-NAME, and TXL + L-NAME groups. Cardiac function was measured through echocardiography. Thioflavin S, Evans Blue, and TTC staining were adopted to evaluate NR and ischemic areas. Cell inflammation degree and edema were assessed by hematoxylin-eosin staining. Automated biochemical analyzer and kit were used to detect the activities of myocardial oxidants, including reactive oxygen species, super oxide dismutase, malonaldehyde, and NO. The expression levels of genes and proteins in the PI3K/Akt/eNOS signaling pathway and apoptosis were detected via real-time fluorescence quantitative PCR and Western blot analysis, respectively. A microvascular tension sensor was adopted to detect coronary artery diastolic function in vitro. RESULTS: TMYX reduced NR and ischemic areas; suppressed LV-mass; enhanced EF, FS, LVOT peak, and LVSV; and improved cardiac structure and function. Moreover, it decreased creatine kinase (CK), CK-MB, and lactic dehydrogenase activities. TMYX increased NO and super oxide dismutase activities; inhibited malonaldehyde activity; reduced muscle fiber swelling and inflammatory cell infiltration; and improved vasodilation in vitro. In the NR myocardium, TMYX stimulated myocardial PI3K activities and PI3K (Tyr458) phosphorylation and enhanced Akt activities and Akt phosphorylation at Tyr315. TMYX increased the activities of eNOS and the phosphorylation of eNOS at Ser1177 in the NR myocardium and attenuated cardiomyocyte apoptosis by increasing the expression of Bcl-2 and decreasing that of caspase-3 and Bax. All these effects of TMYX were abolished by the specific inhibitors of PI3K (LY) and eNOS (L-NAME). CONCLUSIONS: TMYX attenuates myocardial NR after ischemia and reperfusion by activating the PI3K/Akt/eNOS pathway and regulating apoptosis, further up-regulating NO activity and relaxing coronary microvessels. SN - 1872-7573 UR - https://www.unboundmedicine.com/medline/citation/32619593/Tongmai_Yangxin_pill_reduces_myocardial_no-reflow_by_regulating_apoptosis_and_activating_PI3K/Akt/eNOS_pathway L2 - https://linkinghub.elsevier.com/retrieve/pii/S0378-8741(20)30888-6 DB - PRIME DP - Unbound Medicine ER -
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