Therapeutic targets by traditional Chinese medicine for ischemia-reperfusion injury induced apoptosis on cardiovascular and cerebrovascular diseases

Abstract

Traditional Chinese medicine (TCM) has a significant role in treating and preventing human diseases. Ischemic heart and cerebrovascular injuries are two types of diseases with different clinical manifestations with high prevalence and incidence. In recent years, it has been reported that many TCM has beneficial effects on ischemic diseases through the inhibition of apoptosis, which is the key target to treat myocardial and cerebral ischemia. This review provides a comprehensive summary of the mechanisms of various TCMs in treating ischemic cardiovascular and cerebrovascular diseases through anti-apoptotic targets and pathways. However, clinical investigations into elucidating the pharmacodynamic ingredients of TCM are still lacking, which should be further demystified in the future. Overall, the inhibition of apoptosis by TCM may be an effective strategy for treating ischemic cardio-cerebrovascular diseases.

Keywords: apoptosis; cerebral ischemia; molecular mechanisms; myocardial ischemia; traditional Chinese medicine.

FIGURE 1

The representative Chinese herbs in treating myocardial ischemia and cerebral ischemia. Most herbs promote blood circulation and remove blood stasis, such as Panax ginseng C.A.Mey. [Araliaceae], Astragalus mongholicus Bunge [Fabaceae], Conioselinum anthriscoides [Apiaceae], Rhodiola crenulata (Hook.f. & Thomson) H. Ohba [Crassulaceae], Carthamus tinctorius L. [Asteraceae], Ginkgo biloba L. [Ginkgoaceae], Angelica sinensis (Oliv.) Diels [Apiaceae] and Salvia miltiorrhiza Bunge [Lamiaceae] can treat ischemic cardio-cerebrovascular injury and various complications through anti-apoptosis.

FIGURE 2

Endogenous and exogenous apoptotic events are involved in ischemic cardio-brain injuries. Major apoptosis pathways include mitochondria-dependent and death receptor-mediated. These apoptosis pathways together interacted mutually when ischemic diseases occurred. For the former, hypoxia-induced ROS surge and DNA damage directly activated caspase-2 and downstream Bid-activated mitochondrial apoptosis. In parallel, the activated p53 also stimulated the mitochondrial apoptotic process. Meanwhile, DNA damage, ER stress and hypoxia metabolic stress can evoke the mitochondrial apoptosis pathway by activating BH-3 only protein. As for the specific process of mitochondrial apoptosis, Bax and Bak dimers induced by hypoxia formed the channels of cyt-c and AIF in and out on the mitochondrial membrane, which further infuriated the overexpression of Apaf-1, caspase-9 and the apoptosis executor caspase-3 to seduce apoptosis. On the contrary, the increased Smac could negatively inhibit IAPs to further subdue mitochondrial apoptosis. For the latter, pro-caspase-8 and pro-caspase-10 could be activated by the combination of death receptors (FasL/TRAIL) and death ligands (Fas/TRAILR). Together with ER stress and caspase-2, caspase-3/6/7 was thus triggered to result in apoptosis. On the other hand, the formation of TRADD, TRAF, CIAP1/2 and RIPK1 complexes activated by TNF can also lead to apoptosis by irritating caspase-3/6/7/8.