A summary of research on benefiting Qi and activating blood to regulate mitophagy to prevent and treat ischemic heart disease

Ye-Hui He ， Jian-Qi Lu

1.Guangxi University of Chinese Medicine, Nanning 530200, China

2. The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning 530023, China

Keywords:

ABSTRACT

Ischemic heart disease (IHD) is mainly caused by myocardial ischemia and hypoxia caused by coronary artery stenosis or obstruction,and it is still the leading cause of disease death worldwide[1].In the past 20 years,China ischemic The incidence of heart disease has increased by 20.6%,becoming the second leading cause of death in China,seriously endangering the health of our people,and causing a huge burden of disease[2,3].Myocardial cells are rich in mitochondria,and the heart maintains normal physiology Function requires a large amount of energy,and the supply of energy depends on mitochondria in myocardial cells,and timely removal of damaged mitochondria is essential to maintain the normal function of the heart,and abnormal mitophagy can lead to the occurrence of cardiovascular disease.Many studies in recent years It has been shown that traditional Chinese medicine can intervene in mitophagy to prevent and treat related diseases,and it is also closely related to the occurrence and development of heart disease[4,5].By collating relevant literature,this article summarizes the role of mitophagy in ischemic heart disease and the intervention research of TCM Yiqi Huoxue medicine in this regard.

1. Mitophagy

Mitochondria are organelles with double-layer membrane structures in eukaryotic cells,and are the main place for energy production.They synthesize ATP through oxidative phosphorylation,provide energy for the body's life activities,and regulate a series of cell metabolism activities[6].Mitophagy was first proposed by Lemasters[7],and the mechanism of selective phagocytosis and degradation of damaged mitochondria after mitochondrial repair is mitophagy.The main role of mitophagy is through cell autophagy The mechanism selectively removes damaged or dysfunctional mitochondria,thereby controlling the quality of mitochondria and maintaining the integrity of mitochondrial function[8].If mitophagy dysfunction can lead to the occurrence of many diseases,including cardiovascular disease[9].At present,there are three classic pathways of mitophagy,namely PINK(PTEN-inducible kinase)1/Parkin,BNIP(BCL2 interacting protein)3/NIX(Nip3-like protein X),and FUNDC(FUN14 domain containing).

1.1 PINK1/Parkin Pathway

It is currently believed that mitophagy mediated by the PINK1/Parkin pathway is the main pathway for clearing damaged or dysfunctional mitochondria[10].PINK1 is a serine/threonine kinase with N-terminal mitochondrial localization sequence,αhelix transmembrane domain and kinase domain.In normal mitochondria,PINK1 can be shifted into the interior of mitochondria via the outer membrane of mitochondria,and then rapidly in mitochondria Degradation under the action of processing peptidases and proteases.When mitochondria are damaged,PINK1 cannot be transferred into the mitochondria and accumulates on the outer mitochondrial membrane,which accumulates on the outer mitochondrial membrane.Parkin protein is phosphorylated and activated.The activated Parkin ubiquitin mitochondrial outer membrane fusion protein,and finally initiates mitophagy[11,12].

1.2 BNIP3/NIX Pathway

BNIP3 and NIX are two apoptotic proteins located on the outer membrane of the mitochondria,and are members of the B-cell lymphoma-2(BCL2)family[13]with pro-apoptotic activity.BNIP3/NIX plays an important role in the regulation of mitophagy,especially mitophagy induced in the cell under hypoxic or hypoxic conditions,and BNIP3/NIX plays a more significant role.BNIP3 and NIX proteins pass their own LC3-interaction region(LIR)is phosphorylated and combined with microtubule-associated protein 1 light chain 3(LC-3)to initiate mitophagy[14,15].

1.3 FUNDC1 Pathway

FUNDC1 is a mitochondrial outer membrane protein with an LC3-interaction region(LIR)at its N-terminus.LIR and LC3 protein can initiate mitophagy.FUNDC1 mainly induces mitochondria in the state of ischemia,hypoxia and reduced mitochondrial membrane potential Autophagy[16].Under normal circumstances,the 13th serine(Ser13)and 18th tyrosine(Tyr18)in FUNDC1 are phosphorylated to inhibit their binding to LC3.However,under hypoxia,Ser13 and Tyr18 is dephosphorylated,and the LIR region directly interacts with LC3 to induce mitophagy initiation[17].

2. Mitophagy and IHD

There are a large number of mitochondria in myocardial cells,which provide sufficient energy for maintaining normal heart function.When mitochondria are damaged or functionally deficient,the activity of myocardial cells will be reduced,which will lead to the senescence of myocardial cells and even release pro-apoptotic factors and cause cells.Programmed death eventually leads to myocardial damage[18,19].Some studies have shown that cardiomyocyte H9c2 increases the mitochondrial membrane potential by increasing WDR26(WD repeat domain 26)protein after ischemic preconditioning(IPC)under hypoxia.As a result,Parkin is induced to transport to mitochondria,and mitochondrial protein ubiquitination promotes the occurrence of mitophagy.Therefore,damaged cardiomyocytes can initiate mitophagy to clear damaged mitochondria and ultimately protect the ischemic myocardium.However,if mitophagy is excessive,normal mitochondria will be degraded while specific damaged mitochondria are cleared,causing further damage to cardiomyocytes[21].This suggests that in order to avoid further damage to the ischemic myocardium,mitophagy should be appropriately enhanced or inhibited under different circumstances.

Studies have shown that compared to wild-type mice,the area ofmyocardial infarction in PINK1 knockout mice is significantly larger,and the lack of PINK1 in the heart is more susceptible to ischemia/reperfusion injury(I/R).Similarly,another study found that Parkin knockout The survival rate of mice after myocardial infarction decreases,and the area ofmyocardial infarction also increases[22,23].Damaged mitochondria in cardiomyocytes can be selectively eliminated by autophagy mediated by Parkin.Plays a vital role[24].Zhang et al.[25]found that Parkin protein can reduce myocardial cell apoptosis during myocardial infarction,reduce the area ofmyocardial infarction,and make cardiac function-related indicators better.Therefore,PINK1/Parkin plays a role in clearing myocardial cells from damaged mitochondria.It plays an important positive role in protecting the ischemic myocardium,reducing a large amount of myocardial damage,and restoring certain cardiac functions,which is beneficial to the prevention and prognosis of IHD.

In myocardial ischemia/reperfusion injury,the expression of bnip3 increases to promote mitophagy,thereby inhibiting myocardial cell apoptosis[26].Nix deficiency accumulates dysfunctional mitochondria,and cardiac function occurs with age The probability of disorder will increase[27].In addition,fundc1-mediated mitophagy is also closely related to the protection of cardiomyocytes,and some studies have found that mitophagy of fundc1-dependent of cardiomyocytes and platelets can be induced in ischemia and hypoxia,thereby reducing myocardial damage due to ischemia[28].

The above studies have shown that mitophagy has a positive effect on protecting ischemic myocardium,but excessive mitophagy can cause further damage to the myocardium.It can be seen that mitophagy is closely related to the occurrence and development of ihd.

3. Traditional Chinese Medicine and Mitophagy

Ischemic heart disease can belong to the category of"chest palsy"and"heartache"in traditional Chinese medicine.Its main clinical syndrome type is qi deficiency and blood stasis,so the main pathogenesis of ischemic heart disease is qi deficiency and blood stasis.The disease is the most common type of TCM syndrome[29,30].Therefore,the main method of TCM treatment for ischemic heart disease should be used in clinical practice.Some scholars believe that mitochondria is equivalent to what Chinese medicine calls"qi".The function of phagocytosis is very similar to that of traditional Chinese medicine&q uot;Qi.Mitochondria can produce energy which is the embodiment of gasification function.The process of mitophagy is to clear damaged mitochondria to maintain the homeostasis of cells.The method of nourishing qi and activating blood is consistent with that of qi and activating blood,which is to regulate mitochondrial function and clear damaged mitochondria.The role played by mitophagy is the microscopic embodiment of the method of nourishing qi and activating blood.

4. Yiqi Huoxue Traditional Chinese Medicine Monomer and Compound Regulation Mitophagy Prevention and Treatment IHD

4.1 Chinese Medicine Monomer

Regarding the role of Yiqi Huoxue TCM monomers in regulating mitochondria and autophagy,related studies have been carried out by scholars in recent years.Ginsenoside Rb1 can inhibit the excessive autophagy of myocardial hypoxia cells and increase the tolerance of myocardial cells to hypoxia.Ability to reduce myocardial cell death due to hypoxia[34].Zhang Dongwei et al.[35]found through research that ginsenoside Rg1 and astragaloside IV can reduce the expression of PINK1 and Parkin proteins and inhibit the mediation of PINK1-Parkin pathway.The mitophagy can be prevented to prevent excessive mitophagy,thereby playing a role in protecting ischemic myocardium.Studies have shown that astragalus polysaccharide,one of the active ingredients of astragalus,can reduce calcium overload and reduce the production of reactive oxygen species(ROS),so that The mitochondrial membrane potential is reduced and the excessive opening of the mitochondrial membrane permeability transition pores(mPTP)is suppressed,thereby reducing the degree of damage to the mitochondrial membrane structure caused by ischemiareperfusion injury,and finally protecting the normal function of mitochondria to ensure that mitochondria can synthesize ATP provides enough energy for the maintenance of heart function,so that the heart can better exert its contractile function[36].Some scholars have found through experimental research that tanshinone IIACan inhibit the occurrence of mitophagy in cardiomyocytes,thereby promoting the recovery of myocardial function in ischemic and hypoxic myocardium[37].However,salvianolic acid can increase the expression of Parkin protein,thereby promoting the activation of mitophagy in myocardial cells and reducing Damage to the accumulation of mitochondria and ultimately protects the ischemic myocardium[38].Panax notoginseng saponins can significantly increase ATPase activity under myocardial ischemia and hypoxia,thereby promoting mitochondrial conversion and energy production,and reducing ischemia deficiency.Oxygen-induced mitochondrial dysfunction and myocardial cell damage.Panax notoginseng saponins can promote mitophagy and protect ischemic myocardium,and its mechanism may be related to hypoxia-induced factor 1(HIF-1)/adenovirus E1B interaction protein 3(BNIP3)pathway is related[39].From the above research,we can know that the active ingredients of some traditional Chinese medicines for regulating qi and activating blood can regulate mitochondria and autophagy,and have a certain protective effect on the myocardium.

4.2 Chinese Medicine Compound

In addition to the application of monomers and extracts of traditional Chinese medicine,research has also been conducted on the mechanism of mitochondria and autophagy in traditional Chinese medicine compounds.Studies have found that ginseng panax notoginseng extract can regulate mitophagy,and its mechanism may affect Parkin The expression of the protein is related to the displacement of Parkin protein into the interior of the mitochondria[40].Chen Xi[41]found through experimental research that Yiqi Huoxue Fang(composed of ginseng,astragalu s,angelica,chuanxiong,and notoginseng)can reduce myocardial cell apoptosis,It can reduce the damage of mitochondrial structure of cardiomyocytes,and can promote or inhibit the occurrence of mitophagy in cardiomyocytes,and play a role in protecting ischemic myocardium.Yang Hongxing[42]research found that Tongxinluo can mediate mitophagy through the PINK1/Parkin pathway Clearing damaged mitochondria has a significant effect on maintaining homeostasis and protecting ischemic cardiomyocytes.This study shows that Tongxinluo can regulate mitophagy and reduce myocardial ischemia-reperfusion injury. Gao Junjie et al.[43]adopted Animal experiments observed the effect of Danshen Yin on myocardial ischemia/reperfusion injury in myocardium,and found that Danshen Yin can inhibit mitochondrial cell membrane of ischemic myocardium. The conversion hole is open, which has a certain protective effect on ischemic myocardium. In addition, some studies have found that the method of nourishing qi and activating blood can enhance the function of mitochondria by activating pathways related to myocardial energy metabolism, thereby improving the energy supply and metabolism of myocardial cells[44]The above research shows that some traditional Chinese medicine compounds with the effect of nourishing qi and activating blood can also improve mitochondrial function and regulate autophagy, and protect the ischemic myocardium.

5. Conclusion

In summary, mitophagy plays an important role in maintaining the homeostasis of myocardial cells and protecting ischemic myocardium. Moderate mitophagy is beneficial to the body, but excessive mitophagy will cause greater damage to the myocardium. It is not conducive to the recovery of ischemic myocardium.As for how to grasp the optimal degree of mitophagy and maximize the advantage of mitophagy to the myocardium, further research and exploration are needed. At present, Chinese medicine intervention on mitophagy ischemic. The research of heart disease is still in the exploratory stage. At this stage, traditional Chinese medicine compounds and active ingredients of traditional Chinese medicine are mostly used for research. Ignoring the overall concept of traditional Chinese medicine, research should be based on the overall compatibility of traditional Chinese medicine to show the characteristics of traditional Chinese medicine. This requires more and more researchers to carry out deeper and broader exploration and research, and provide new targets for traditional Chinese medicine treatment of ischemic heart disease, which is of great significance for inspiring new ideas for relevant scientific researchers and clinicians.