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Induction of Autophagy by Tongxinluo Through the MEK/ERK Pathway Protects Human Cardiac Microvascular Endothelial Cells From Hypoxia/Reoxygenation Injury

Cui, Hehe MD, PhD; Li, Xiangdong MD, PhD; Li, Na MD, PhD; Qi, Kang MD, PhD; Li, Qing MD; Jin, Chen MD; Zhang, Qian MD, PhD; Jiang, Leipei MD; Yang, Yuejin MD, PhD

Journal of Cardiovascular Pharmacology: August 2014 - Volume 64 - Issue 2 - p 180–190
doi: 10.1097/FJC.0000000000000104
Original Article

Abstract: In contrast to cardiomyocytes, autophagy in cardiac microvascular endothelial cells (CMECs) during ischemia/reperfusion (I/R) injury has not been fully investigated. Tongxinluo (TXL), a traditional Chinese medicine, was shown to be vascular protective. We aimed to elucidate the role of autophagy and its regulatory mechanisms by TXL in CMECs subjected to I/R injury. CMECs were exposed to different treatments for 30 minutes and subjected to hypoxia/reoxygenation each for 2 hours. The results indicated that hypoxia/reoxygenation significantly induced autophagy, as identified by an increased number of monodansylcadaverine-positive CMECs, increased autophagosome formation, and a higher type II/type I of light chain 3 ratio, but not Beclin-1 expression. Autophagy inhibition using 3-methyladenine was proapoptotic, but rapamycin-induced autophagy was antiapoptotic. TXL enhanced autophagy and decreased apoptosis in a dose-dependent manner, reaching its largest effect at 800 μg/mL. 3-methyladenine attenuated the TXL-promoted autophagy and antiapoptotic effects, whereas rapamycin had no additional effects compared with TXL alone. TXL upregulated mitogen-activated protein kinase and extracellular signal-regulated kinase (ERK) phosphorylation; however, PD98059 abrogated ERK phosphorylation and decreased autophagy and increased apoptosis compared with TXL alone. These results suggest that autophagy is a protective mechanism in CMECs subjected to I/R injury and that TXL can promote autophagy through activation of the mitogen-activated protein kinase/ERK pathway.

State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Reprints: Yuejin Yang, MD, PhD, Center of Coronary Heart Disease, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 167, Beilishi Rd, Xicheng District, Beijing 100037, China (e-mail: fwyangyuejin@126.com).

The authors report no conflicts of interest.

Received November 21, 2013

Accepted March 24, 2014

© 2014 by Lippincott Williams & Wilkins.