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The role of protein homeostasis in pathological heart remodeling
The role of protein homeostasis in pathological heart remodeling. Pathological heart remodeling is the main pathological change of a variety of heart diseases, manifested as myocardial hypertrophy and fibrosis, and eventually lead to heart failure.
As a terminally differentiated cell, cardiomyocytes have limited ability to proliferate and regenerate. Therefore, protein homeostasis is extremely important for the survival and function of cardiomyocytes. Cellular protein homeostasis means that the process of protein synthesis and degradation reaches a dynamic balance, which is mainly regulated by the protein quality control system including molecular chaperones, ubiquitin proteasome, and autophagy.
Recent studies have shown that myocardial cell protein homeostasis plays an important role in the maintenance of cardiac homeostasis. Abnormalities in any part of the protein quality control system may cause protein toxicity, leading to pathological heart remodeling. This article reviews the new progress in the role of protein homeostasis in the maintenance of cardiac homeostasis, and prospects for the treatment of heart diseases by regulating protein homeostasis.
Heart failure , as the final stage of the occurrence and development of various heart diseases, is an important cause of death in most patients, and pathological heart remodeling is the determinant of heart failure.
Pathological heart remodeling refers to the compensatory response of cardiomyocytes under the stimulation of many factors including myocardial infarction and pressure load, mainly manifested as cardiomyocyte hypertrophy, apoptosis and necrosis, collagen tissue proliferation, and accompanied by inflammation, heart Various changes such as dysfunction.
Slowing down or reversing remodeling is an important strategy for the treatment of heart failure. Therefore, to clarify the pathogenesis of pathological heart remodeling and find its related regulatory molecules is of great significance for the prevention and treatment of heart failure.
As the material basis of life activities, protein involves the normal operation of every biological process. Protein homeostasis is the balance between the two processes of new protein production, folding and aging, misfolding and removal of damaged proteins in the cell .
The imbalance of protein homeostasis is closely related to many diseases, such as neurodegenerative diseases, diabetes and cancer. Cardiomyocytes are a kind of contractile cells that make up the heart muscle. Their healthy survival is very important for maintaining normal heart contraction function.
As a terminally differentiated cell, cardiomyocytes have limited ability to proliferate and regenerate, so the maintenance of protein homeostasis is very necessary for the healthy survival of cardiomyocytes. Only when protein synthesis and degradation are in a balanced state, the half-life of heart protein can be in a stable state, and the destruction of protein homeostasis will cause a variety of heart diseases .
1. Maintaining the protein homeostasis of cardiomyocytes depends on the protein quality control system
The protein homeostasis of cardiomyocytes depends on the regulation of a series of protein quality control systems in the cell. The protein quality control system of cardiomyocytes can generate and store a series of functional proteins to offset the protein toxicity caused by damaged proteins. It mainly acts in the following three ways.
1)Molecular chaperone-mediated protein quality control system of cardiomyocytes:
As the first line of defense of the intracellular protein quality control system, molecular chaperones play a key role in regulating protein synthesis and normal folding. The molecular chaperone helps stabilize the protein and fold it into an effective conformation by interacting with the new protein . In addition, misfolded proteins often expose sticky hydrophobic surfaces, and molecular chaperones will initiate protein refolding or bind to the sticky and hydrophobic regions of these misfolded proteins to block their interaction and aggregation .
Heat shock proteins (HSP) are an important class of molecular chaperones, which can be divided into HSPA (HSP70), small HSP (HSPB), HSPC (HSP90), HSPD (HSP60), HSPE (HSP10), HSPH ( HSP110) and DNAJ (HSP40). Cardiomyocytes can highly express some specific small HSP family (HSPB), such as HSPB1 (HSP27), HSPB5 (CryAB), HSPB6 (HSP20), HSPB7 and HSPB8 (HSP22) . CryAB is the most abundant molecular chaperone in the heart. It can work in conjunction with cytoskeleton and contractile device proteins, and especially can interact with myocardial cell line protein (desmin) to prevent its misfolding and aggregation .
In short, HSP in the heart can protect cardiomyocytes from damage under stress and pathological conditions by promoting the degradation of misfolded proteins, inhibiting cardiomyocyte apoptosis, and maintaining the integrity of the sarcomere structure .
2) Ubiquitin proteasome-mediated cardiomyocyte protein quality control system:
If the misfolded protein does not choose to refold, the molecular chaperone will make it in a soluble state to facilitate the removal of the ubiquitin proteasome system. The ubiquitin proteasome system is a primary degradation system that removes ubiquitinated proteins in a soluble state. It mainly degrades normal proteins that are misfolded, oxidized, and mutated, and are no longer needed by the body to maintain transient regulation of protein activity .
The ubiquitin proteasome system is a highly specific and coordinated enzymatic cascade reaction, which performs multiple ubiquitination tags for specific proteins and uses them as degradation tags, which are then handed over to the proteasome for degradation . The ubiquitination system consists of ubiquitin activating enzyme E1, ubiquitin conjugating enzyme E2 and ubiquitin ligase E3. The proteasome is composed of a multi-subunit 20S core, which has catalytic activity on β1, β2, and β5 subunits .
Ubiquitin ligase confers substrate specificity during ubiquitination and is the rate-limiting enzyme of the ubiquitin proteasome system. There are a variety of ubiquitin ligases in heart tissue, such as MuRF-1, MuRF-2, MuRF-3, Atrogin-1, CHIP, and MDM2. These proteins can maintain the integrity of the contractile device by degrading sarcomeric protein [5 ].
3) Autophagy-mediated protein quality control system:
When the protein cannot be in a soluble state, and the ubiquitin proteasome system cannot process excessive misfolded protein through degradation, the cell will initiate the autophagy pathway to regulate protein homeostasis. Autophagy pathway refers to the process of encapsulating damaged organelles and misfolded and aggregated proteins into autophagic vesicles, and fusing with lysosomes, and then degrading their inclusions by acid hydrolases in lysosomes.
Relative to the specificity of the ubiquitin proteasome system, autophagy is a non-selective catabolic process. Cells can cause autophagy under stress factors such as lack of nutrients and damage to organelles. Autophagy can regulate the degradation and reuse of long-lived proteins and organelles, synthesize new components in cells, and participate in regulating cell secretion and transportation .
Excessive activation or insufficient autophagy will cause the accumulation of abnormal proteins and organelles, which will disrupt the normal cell growth mechanism and cause disease . The autophagy process of cardiomyocytes is complex and regulated by a variety of important molecules.
The Ulk kinase complex including autophagy-related genes Atg13 and other molecules is responsible for initiating the autophagy process, and then activating Beclin1, Atg14L, Vps34 and other macromolecules to ensure the continuous expansion of the autophagosome membrane. Later in the process of autophagosome maturation, Atg3, Atg5, Atg7, Atg12, LC3 and other molecules played an important role.
Finally, under the action of SNARE proteins (STX17, SNAP29, VAMP8), mature autophagosomes and lysosomes combine to form autophagic lysosomes, completing the autophagy process of cardiomyocytes .
2. The imbalance of protein homeostasis in cardiomyocytes leads to pathological heart remodeling
Under physiological or pathological pressures, such as changes in pH, temperature, osmotic pressure, and oxidative stress, it can cause intracellular protein folding errors. When misfolded proteins combine with each other to form protein aggregates such as soluble oligomers, soluble aggregates, and inclusion bodies, they can induce cell death. This process is called protein toxicity . Protein toxicity is closely related to various pathophysiological processes of the heart.
1) Molecular chaperones and pathological heart remodeling:
Abnormal levels of molecular chaperones that regulate protein synthesis and folding in cardiomyocytes can cause protein accumulation and lead to pathological heart remodeling. Studies have found that HSPB6 mutant (HSPB6S10F) exists in patients with dilated cardiomyopathy, and expression of this mutant in the mouse heart will promote BECLIN1 ubiquitination and protease degradation, thereby inhibiting cardiomyocyte autophagy and promoting apoptosis. And eventually lead to pathological heart remodeling and heart failure .
Abnormal mutations and accumulation of molecular chaperone CryAB can cause hypertrophic and restrictive cardiomyopathy [13, 14]. The specific knockout of HSPB7 by cardiomyocytes leads to abnormal formation of actin bundles, which leads to the death of mouse embryos . Myocardial cell specific knockout of HSPD (Hsp60) leads to dilated cardiomyopathy and heart failure by affecting mitochondrial function and protein homeostasis .
Cardiomyocyte-specific knockout or mutation of Bag3 will destroy the interaction with Hsp70, reduce the expression of small heat shock proteins, and cause insoluble deposition of functional proteins in the heart, leading to dilated cardiomyopathy in mice . Therefore, the normal function of molecular chaperones in cardiomyocytes is of great significance for the maintenance of cardiac homeostasis.
2) Ubiquitin proteasome and pathological heart remodeling:
abnormal levels of important molecules related to the ubiquitin proteasome system in cardiomyocytes can cause heart disease. Studies have found that ubiquitin proteasome activity is reduced in a variety of cardiomyopathy and heart failure patients. The specific lack of ubiquitin ligase WWP2 in cardiomyocytes can reduce the ubiquitination level of polyadenosine diphosphate ribose polymerase (PARP1), thereby exacerbating isoproterenol-induced myocardial hypertrophy and heart failure .
Overexpression of ubiquitin ligase TRIM6 in cardiomyocytes can promote cardiomyocyte apoptosis and aggravate ischemia-reperfusion injury . The absence of the ubiquitin ligase-related molecule Asb2α causes the degradation of filaggrin FLN, which leads to remodeling of the myocardial cytoskeleton, myofibril disorders, and embryonic death in mice .
Overexpression of ubiquitin-conjugating enzyme variants (Ube2v1) in cardiomyocytes can cause ubiquitin proteasome dysfunction, thereby exacerbating the protein accumulation induced by CryABR120G . The lack of ubiquitin-specific protease 4 (USP4) activates the transforming factor kinase TAK1-(JNK1/2)/P38 signaling pathway, aggravating myocardial hypertrophy and cardiac dysfunction under pressure load .
Proteasome inhibitors can aggravate myocardial hypertrophy, ventricular dilatation and cardiac dysfunction caused by aortic coarctation (TAC) by activating the calcineurin signaling pathway . The lack of Ubquilin1 in cardiomyocytes affects the combination of ubiquitinated substrates and proteasomes, leading to abnormal accumulation of ubiquitinated proteins, causing cardiomyopathy and exacerbating ischemia-reperfusion injury . Therefore, the normal operation of the ubiquitin proteasome pathway is very important for the maintenance of cardiac homeostasis.
3) Autophagy process and pathological heart remodeling:
The abnormal level of autophagy-related regulatory molecules in cardiomyocytes is also closely related to pathological heart remodeling. In patients with hypertrophic cardiomyopathy and mouse hearts caused by mutations of myocardial myosin binding protein (Mybpc3), it was found that the autophagy process of cardiomyocytes was impaired . Myocardial cell specific knockout of Atg5 inhibits autophagy, resulting in left ventricular dilation and impaired heart function .
Overexpression of CD38 in cardiomyocytes destroys the combination of autophagosomes and lysosomes, inhibits autophagy, thereby aggravating cardiac dysfunction under hypoxic-ischemic conditions . Cardiomyocyte-specific knockout of Vps34 affects the autophagy degradation process, causing abnormal accumulation of molecular chaperone CryAB, leading to disorder of myofibril arrangement and hypertrophic cardiomyopathy .
The specific overexpression of microRNA (miR)-199a in mouse cardiomyocytes inhibits cardiomyocyte autophagy through GSK3β/mTOR signaling pathway, leading to pathological myocardial hypertrophy . Although the above results indicate that inhibition of cardiomyocyte autophagy can promote pathological heart remodeling, abnormal activation of autophagy can also cause pathological heart remodeling. Cardiomyocytes overexpression of Beclin1 can increase cardiomyocyte autophagy, but show more severe pathological heart remodeling under hypertrophic stimulation .
Overexpression of TXNIP protein in cardiomyocytes can cause abnormal activation of autophagy by up-regulating the level of autophagosomes, and aggravate cardiomyocyte apoptosis and cardiac dysfunction caused by ischemia-reperfusion . Therefore, maintaining normal levels of autophagy in cardiomyocytes is particularly important for maintaining cardiac homeostasis.
3. Regulating protein homeostasis can treat pathological heart remodeling
The heart protein quality control system plays an important role in maintaining heart homeostasis. The study of linking protein misfolding and aggregation with various cardiomyopathy provides new ideas for the treatment of clinical heart diseases. In recent years, some people have tried to treat heart disease by regulating the expression of molecules and downstream effector molecules in the process of protein quality control, and found that the regulation of protein homeostasis can effectively alleviate pathological heart remodeling.
1) Regulation of molecular chaperones can alleviate pathological cardiac remodeling:
enhancing the expression of molecular chaperones can prevent protein accumulation and reduce protein toxicity, which is beneficial to the treatment of pathological cardiac remodeling. Up-regulation of Hsp70 (HSPA) expression in cardiomyocytes can reduce the infarct size caused by ischemia-reperfusion and improve cardiac function . Injection of Bag3 overexpressing adenovirus in mice can reduce myocardial cell apoptosis and relieve myocardial infarction and cardiac dysfunction caused by ischemia-reperfusion .
In addition, molecular chaperone inducers and chemical drugs can function by enhancing or replacing molecular chaperones to alleviate pathological heart remodeling. Heat shock protein inducer teprenone (GGA) and its derivatives can up-regulate the expression of heat shock protein, repair ventricular remodeling and improve heart function . Tafamidis can help transthyretin to fold correctly and stabilize its conformation by exerting its molecular chaperone function, thereby improving the heart function and reducing mortality in patients with thyroxine precipitated cardiomyopathy .
The small molecule drug chaperone migalastat can stabilize intracellular enzymes, reduce the accumulation of pathogenic substances, and improve the symptoms of cardiac hypertrophy caused by Fabry disease . The above studies have shown that the enhancement of the function of myocardial cell chaperones can alleviate pathological heart remodeling.
2) Regulating the ubiquitin proteasome pathway can alleviate pathological cardiac remodeling:
Enhancing the ubiquitin proteasome pathway can also target pathological cardiac remodeling. The expression of ubiquitin ligase CHIP in cardiomyocytes in vitro can reduce myocardial hypertrophy and apoptosis induced by lipopolysaccharide .
Overexpression of ubiquitin ligase TRIM32 in rat primary cardiomyocytes can degrade dysbindin protein to inhibit myocardial hypertrophy . In addition to enhancing the expression of ubiquitin ligase, activation of proteasome activity in cardiomyocytes can also alleviate pathological heart remodeling.
Overexpression of the proteasome subunit PA28α can enhance the function of the proteasome and relieve the cardiomyopathy and cardiac dysfunction caused by diabetes . Molecular tweezers Tweezer CLR01 can enhance the proteasome activity in the heart of CryABR120G transgenic mice, promote the degradation of misfolded proteins, and prevent the process of cardiac protein disease .
Inhibiting phosphodiesterase (PDE1) can also enhance the 26S proteasome activity and the proteolytic function of the ubiquitin proteasome, promote the degradation of misfolded proteins in the heart of CryABR120G transgenic mice, and delay the occurrence of cardiac protein diseases . The above studies show that the regulation of ubiquitin ligase and proteasome activity can alleviate pathological heart remodeling.
3) The regulation of autophagy pathway is beneficial to improve pathological cardiac remodeling:
regulating the level of cardiomyocyte autophagy can alleviate the pathological cardiac remodeling caused by protein toxicity. A number of studies have shown that activating cardiomyocyte autophagy can treat pathological heart remodeling. Overexpression of Atg7 or transcription factor TFEB in the heart of CryABR120G transgenic mice can enhance cardiomyocyte autophagy, reduce abnormal accumulation of proteins in the heart, and relieve cardiac dysfunction [41, 42].
Orientin can alleviate myocardial hypertrophy and fibrosis in a mouse model of pathological myocardial hypertrophy by activating cardiomyocyte autophagy . Metformin can enhance cardiomyocyte autophagy in a mouse model of dilated cardiomyopathy by regulating the AMPK/mTOR signaling pathway, improve left ventricular remodeling and protect heart function . Trehalose TRE activates cardiomyocyte autophagy in a mouse model of permanent left anterior descending coronary artery ligation by up-regulating the expression of TFEB, and alleviates cardiac remodeling and cardiac dysfunction caused by myocardial infarction .
Similarly, spermidine can enhance cardiomyocyte autophagy by activating the AMPK/mTOR signaling pathway, and alleviate apoptosis and cardiac dysfunction caused by myocardial infarction . However, studies have shown that inhibiting autophagy can also prevent pathological heart remodeling. RAGE soluble receptor (sRAGE) can reduce the apoptosis and myocardial injury caused by ischemia-reperfusion by inhibiting myocardial autophagy .
Trimetazidine inhibits excessive autophagy by up-regulating the AKT/mTOR signaling pathway, and inhibits cardiomyocyte apoptosis and ischemia-reperfusion injury . Therefore, activating or inhibiting the excessive activation of autophagy to ensure that the autophagy of cardiomyocytes is maintained at a normal level can alleviate pathological heart remodeling to varying degrees.
Protein homeostasis plays an important role in the regulation of pathological heart remodeling. Targeting and regulating the myocardial protein quality control system to prevent myocardial damage caused by protein toxicity is expected to become a new strategy for clinical heart disease treatment.
Therefore, to further clarify the mechanism of protein homeostasis in the maintenance of cardiac homeostasis, and to screen key regulatory molecules that regulate cardiac protein homeostasis is of great significance for the treatment of pathological cardiac remodeling.
In recent years, the emerging CRISPR/Cas9 somatic cell gene editing technology can achieve relatively accurate gene editing in somatic cells of adult tissues, and has played an important role in pathogenic gene screening and gene therapy [49, 50].
Combining this somatic gene editing technology with cardiac protein homeostasis research will help to quickly identify protein homeostasis regulators that play a key role in heart disease. Further use of this technology to intervene and evaluate the efficacy of the key regulatory molecules screened in classic mouse disease models will help to find ideal molecular targets for pathological cardiac remodeling gene therapy.
(source:internet, reference only)