FRAP (mTOR), also called Mammalian target of rapamycin (mTOR) is an important regulator of cell growth and proliferation. Numerous studies have shown that the abnormal regulation of mTOR signaling pathway is closely related to cell proliferation. The mammalian target of rapamycin (mTOR) is an atypical serine/threonine kinase, which belongs to the phosphoinositide kinase-related kinase family and is involved in regulating the metabolism of body cells and proteins. It is currently known to be closely related to the occurrence and development mechanism of various cardiovascular diseases such as hypertrophic cardiomyopathy (HCM), myocardial ischemia-reperfusion, dilated cardiomyopathy (DCM), and heart failure.

Figure 1. Protein structure of mTOR.

Introductions

In the early days, through the continuous deepening of medical research, cardiovascular diseases can be detected more and more early, but due to its complex pathogenesis, its treatment strategy needs to be further improved. Rapamycin (mTOR) is a serine/threonine kinase that is highly conserved in evolution. It has been replaced due to its immunosuppressive effect, and with the continuous research at home and abroad, it has been found that mTOR is also used in many cardiovascular diseases. It plays a certain role, such as hypertrophic cardiomyopathy (HCM), myocardial infarction reperfusion, dilated cardiomyopathy, heart failure, etc., and has become a research hotspot.

Definations

mTOR belongs to the phosphoinositide 3 kinase (PI3K) family, and has functions such as immunosuppression, regulating cell growth, protein synthesis, forming the cytoskeleton, transmitting nutrients and energy. mTOR includes two different types of multi-protein complexes, mTORC1 and mTORC2. mTORC1 receives a variety of signals from growth factors, insulin and inflammatory factors, and transduces the signals to downstream target genes S6K1 and 4EBP1, etc., thereby regulating glycolysis and biosynthesis of proteins, lipids, and nucleotides and maintain the homeostasis of the cells. mTORC2 regulates lipid metabolism, insulin resistance, and glycogen synthesis. mTORC1 and mTORC2 play their respective roles through different signaling pathways, but the pathways are interrelated. Recent studies have shown that mTOR is involved in the occurrence and development of various cardiovascular diseases.

Conclusions

mTOR has the functions of sensing the nutrition and energy status of cells, detecting the availability of growth factors, feeling stress stimuli, other cells, and environmental cues, and may play an important regulatory role in the metabolism of myocardial cells and the pathway of stress response. Although the elaboration of the mechanism of action in existing studies is not complete, it also suggests the great potential of mTOR in cardiovascular disease research. Further research on mTOR and its inhibitors provides new directions for the diagnosis and treatment of various cardiovascular diseases in the clinic.

Complexes

mTOR is the catalytic subunit of two complexes with different structures: mTORC1 and mTORC2.

mTORC1

mTOR complex 1 (mTORC1) is composed of mTOR, mTOR's regulatory related protein (Raptor), mammals with SEC13 protein 8 (mLST8) lethality, and non-core components PRAS40 and DEPTOR. mTORC1 activity is regulated by rapamycin, insulin, growth factors, phosphatidic acid, certain amino acids and their derivatives, mechanical stimulation and oxidative stress.

mTORC2

The mTOR complex 2 (mTORC2) consists of MTOR, rapamycin-insensitive MTOR partner (RICTOR), MLST8, and mammalian stress-activated protein kinase interaction protein 1 (mSIN1). mTORC2 has been shown to be actin Important conditioner. Stimulate the cytoskeleton by stimulating F-actin stress fibers, paxillin, RhoA, Rac1, Cdc42 and protein kinase Cα (PKCα).

mTOR and myocardial ischemia-reperfusion injury

Myocardial infarction (MI) is due to coronary occlusion and interruption of blood flow, causing partial myocardial necrosis due to severe persistent ischemia. Coronary arterial blood reperfusion forcibly saves part of the ischemic myocardium, but there will be a series of drastic changes, such as the generation of reactive oxygen species, the change in NO bioavailability, intracellular Ca²⁺ and Na⁺ redistribution, and Change, etc. Reperfusion itself can also cause myocardial cell apoptosis with irreversible myocardial damage. This phenomenon is called "myocardial ischemia-reperfusion injury. Existing studies have shown that myocardial cell autophagy plays a role in It plays a protective role at times, but it does damage during reperfusion, and mTOR plays an important regulatory role in autophagy. mTOR can be activated by glycogen synthase kinase 3 beta (GSK-3β), thereby Inhibition of autophagy during myocardial ischemia-reperfusion injury protects the myocardium rather than ischemic injury.

Reference

1. Sabers CJ1; et al. Isolation of a Protein Target of the FKBP12-Rapamycin Complex in Mammalian Cells. J Biol Chem. 1995, 3;270(2):815-22