Chinese Herbal Medicine Alleviates Myocardial Ischemia/Reperfusion Injury by Regulating Endoplasmic Reticulum Stress

Abstract

Myocardial ischemia/reperfusion injury is the main cause of increased mortality and disability in cardiovascular diseases. The injury involves many pathological processes, such as oxidative stress, calcium homeostasis imbalance, inflammation, and energy metabolism disorders, and these pathological stimuli can activate endoplasmic reticulum stress. In the early stage of ischemia, endoplasmic reticulum stress alleviates the injury as an adaptive survival response, but the long-term stress on endoplasmic reticulum amplifies oxidative stress, inflammation, and calcium overload to accelerate cell damage and apoptosis. Therefore, regulation of endoplasmic reticulum stress may be a mechanism to improve ischemia/reperfusion injury. Chinese herbal medicine has a long history of clinical application and unique advantages in the treatment of ischemic heart diseases. This review focuses on the effect of Chinese herbal medicine on myocardial ischemia/reperfusion injury from the perspective of regulation of endoplasmic reticulum stress.

Figure 1

UPR signaling pathway. With ER stress, GRP78 dissociates from three ER transmembrane sensors—IRE1, PERK, and ATF6—to allow their activation. Active IRE1 cleaves the mRNA encoding XBP1 to produce activated XBP1s, which enters the nucleus and induces the transcription of UPR target genes. Active PERK phosphorylates eIF2α to inhibit protein synthesis while upregulating ATF4 to active the UPR target genes. ATF4 also induces GADD34 to dephosphorylate eIF2α. ATF6 is hydrolyzed in the Golgi to produce an active fragment that enters into the nucleus to induce expression of UPR target genes.

Figure 2

Myocardial I/R injury and ER stress. Myocardial I/R activates ER stress, and ER stress activates the UPR. Short-term UPR restores ER stability by activating ERAD, increasing the ER protein folding ability and inhibiting protein synthesis, which alleviates myocardial I/R injury. However, long-term UPR aggravates myocardial I/R injury by activating oxidative stress, calcium overload, inflammation, excessive autophagy, and apoptosis.

Figure 3

Chinese herbal medicines regulate ER stress to improve myocardial I/R injury.