The research status of Asprosin and its application prospect in the protection of myocardial injury

ZHANG Min, JIANG Feng , PENG Qing

Department of Cardiovascular Medicine, Affiliated Hospital of Southwest Medical University, Luzhou 646000, China

ABSTRACT Asprosin is a newly discovered protein hormone that promotes appetite, regulates glucose homeostasis, increases insulin resistance and has potential myocardial protection.Myocardium is vulnerable to oxidative stress injury caused by factors such as high glucose, anti?tumor drugs, ischemia reperfusion and so on, and currently there is a lack of effective preventive measures.It has been reported in the literature that Asprosin has a unique protective effect on myocardium, but the protective mechanism of Asprosin is not clear.In this paper, the general situation and functions of Asprosin, as well as the protective mechanism of Asprosin on myocardium were reviewed, in order to provide reference for the application of Asprosin in the treatment of cardio?related diseases.

Keywords:

Asprosin

Myocardial damage

Antioxidant therapy

1.Introduction

Asprosin is a newly discovered protein food stimulating hormone,which has a negative effect on metabolic diseases, but has a unique protective mechanism for the myocardium.At present, there are few studies on Asprosin in human body and the specific mechanism remains unclear.In this paper, the general situation and function of Asprosin, as well as the possible mechanism of Asprosin in myocardial protection are reviewed.

2.An overview of Asprosin

2.1 The source and distribution of Asprosin

Asprosin is a fasting?induced protein hormone discovered by Romere et al.in the study of children with pregeria?like syndrome in 2016, which is the carbon terminal cleavage product of promyofibrillar protein[1].It is mainly secreted by white adipocytes,and Asprosin immune response can be seen in the interlobular tubule and interlobular tubule of the submandibular gland and parotid gland[1, 2].In addition, muscle tissue may also be one of its secretory organs[3], and its presence can be detected in multiple tissues (such as liver, kidney, heart, stomach, testis and brain tissues)of the mouse body[4].

2.2 Influencing factors of Asprosin

The level of Asprosin circulating in the blood correlates with nutritional status.In the physiological state, fasting promotes its release, while eating suppresses its production, showing a circadian rhythm [5], which is affected by food, blood glucose level, temperature, exercise, thyroid function and other factors[1,3, 6-10].In obese and insulin resistant adults and mice, the levels of Asprosin in blood circulation are pathologically elevated[1, 5].In diabetic nephropathy and diabetic ophthalmopathy, the serum concentration of Asprosin increases with the progression of the disease[11, 12].Asprosin elevated in patients with polycystic ovary syndrome, gestational diabetes mellitus and their offspring[13, 14].It was positively correlated with body mass index, waist?hip ratio,homeostasis model of insulin resistance (HOMA?IR), low density lipoprotein cholesterol, triglyceride, etc.[2, 3, 15-17].

In the study of obese children, the circulating level of Asprosin is controversial.Long et al.[18] showed that the concentration of Asprosin in obese children was significantly lower than that in normal weight children, while the study of Wang et al.[17] and Eda Sunnetci et al.[19] was contrary.The above differences may be related to the differences in experimental methods, experimental subjects and detection reagents.Therefore, more clinical observations are needed to further clarify whether the circulating level of Asprosin is increased or decreased in obese children.

2.3 Aspronsin function

2.3.1 Asprosin can promote obesity and aggravate insulin resistance

Asprosin can increase the firing frequency and membrane potential of central food stimulating neurons (AGRP +), inhibit anorexia neurons (POMC+), increase appetite and increase body weight[5].Studies have shown that Asprosin can increase lipid deposition through NF2?mediated mechanism pathway, thereby aggravating obesity[20].In addition, Asprosin can promote the release of liver glucose by activating the cAMP?PKA pathway, and this effect is not affected by catecholamine and glucagon[1].In vitro studies have shown that Asprosin can promote the inflammatory response and dysfunction of pancreatic islet cells through the TLR4 pathway,leading to insulin resistance[21].Moreover, endoplasmic reticulum stress and inflammatory response can also reduce the sensitivity of skeletal muscle cells to insulin[22].Therefore, Asprosin has become a hot spot and potential therapeutic target in the study of obesity,type 2 diabetes and related complications.Most studies believe that the increase of Asprosin can predict the occurrence and progress of the above?mentioned diseases, and reduce the circulation level of Asprosin can prevent or control the occurrence of obesity and related metabolic diseases.At the same time, Asprosin can rapidly increase blood glucose in the state of hunger or hypoglycemia, so as to maintain normal blood glucose in children with prosenoid syndrome,and is expected to play a beneficial role in anorexia, severe burns,sepsis and cachexia[1, 23-25].

In the reproductive system, Asprosin can enhance the motility of mouse sperm and improve fertility through the OLFR734 axis, but whether it can promote the directional motility of sperm remains to be further studied [26].Asprosin can promote the function of bovine follicular membrane cells without affecting progesterone, and may become a new regulator of ovarian follicular function[27].Whether Asprosin has a promising application in human reproductive system diseases needs systematic research, but it may become a new treatment strategy for infertility and other diseases.

In conclusion, Asprosin is secreted by white adipocytes,submandibular glands, parotid glands, etc., and is expressed in multiple tissues of the body, showing circadian rhythm.It has negative effects on metabolic diseases (such as obesity, type 2 diabetes, etc.), and is positively correlated with metabolism?related indicators.However, changes in concentrations in children need to be further studied.

Asprosin can increase appetite, gain weight and promote insulin resistance, which have negative effects on the body, but may play a beneficial role in diseases such as anorexia and cachexia.In addition,Asprosin can also regulate the function of germ cells and has a good effect on cardiomyocytes.

Next, this paper will discuss the feasibility, mechanism and application prospect of Asprosin in the prevention of myocardial injury by combining the related mechanisms of diabetic cardiomyopathy, coronary heart disease and chemotherapeutic drugs leading to myocardial oxidative stress injury, as well as the role of antioxidant therapy in myocardial oxidative injury.

3.Asprosin can participate in the regulation of myocardial oxidative stress injury mechanism

Myocardial cells are rich in mitochondria, accounting for about 30?40% of the cell volume, which is related to the function and vitality of cardiomyocytes [28].Compared with other organs, myocardial cells are vulnerable to oxidative stress injury due to low antioxidant content despite high mitochondrial density[29].Mitochondria are the main source of cellular energy and reactive oxygen species, as well as the main target of reactive oxygen species[28, 30].Reactive oxygen species can cause non?specific damage to lipids, proteins and DNA, leading to changes or loss of cell function[31].Oxidative damage to mitochondria is the driving force of mitochondrial dysfunction, which is a common mechanism leading to cell death[32].When mitochondrial function is impaired, more reactive oxygen species can be produced, which in turn can further induce mitochondrial damage, forming a vicious cycle in which reactive oxygen species induces more reactive oxygen release[30].Under normal circumstances, the body can protect cells from oxidative stress damage by scavenging intracellular reactive oxygen species through the antioxidant defense system.However, when there is an imbalance between endogenous antioxidant enzymes and oxidants produced in mitochondria, apoptosis occurs[32].

3.1 Asprosin and diabetic cardiomyopathy

Diabetic cardiomyopathy is a unique heart disease caused by diabetes mellitus, mainly characterized by accumulation of myocardial lipid and cardiac dysfunction[33].Myocardial energy metabolism disorder and oxidative stress are one of the pathogenesis of diabetic cardiomyopathy [33].Hyperglycemia is one of the central drivers of cardiac metabolism, function and structure changes in diabetes mellitus[34].A healthy heart is powered by 70% fatty acids(FA) and 30% glucose[35].Due to the stimulation of high glucose, the expression of membrane protein (PPAR?A expression is up?regulated and GLUT?4 expression is suppressed) for myocardial uptake and utilization of energy substrates is changed, and diabetic myocardium almost completely relies on fatty acid metabolism for energy supply[35-37].The change of energy substrate makes mitochondria use more free fatty acids for oxidation and produces more reactive oxygen species in myocardium.However, in diabetic myocardium,the expression and activity of superoxide dismutase 2 (SOD2) are decreased[38].Therefore, mitochondria and cardiomyocytes suffer oxidative stress damage[37].Asprosin is involved in the body’s energy metabolism and has become a potential therapeutic target for metabolic diseases such as diabetic cardiomyopathy.

3.2 Asprosin and myocardial ischemia?reperfusion injury

Cardiovascular disease is the leading cause of morbidity and mortality worldwide.Oxidative stress plays an important role in atherosclerosis and myocardial ischemia?reperfusion injury [39].Endothelial injury is the primary factor of atherosclerosis, and the production of reactive oxygen species can accelerate its development[40].However, in the early stage of blood flow recovery in ischemic myocardium, the cascade reaction of reactive oxygen species will be stimulated, and a large amount of reactive oxygen species will be produced in cardiomyocytes, leading to further damage of cardiomyocytes[39].The production of reactive oxygen species in mitochondria is the initiator of ischemia reperfusion injury.However,during reperfusion, the myocardium lacks the ability to produce antioxidants, resulting in accelerated tissue necrosis[40].Asprosin has become a potential target for the treatment of metabolic diseases and may play a role in the prevention and treatment of coronary heart disease.

3.3 Asprosin and cardiac toxicity

Adriamycin is the most commonly used and effective antitumor drug[41].Increased production of reactive oxygen species is considered to be the classic mechanism of cardiomyocyte apoptosis induced by adriamycin[42].Adriamycin not only inhibits the activity of the antioxidant defense system, but also inhibits mitochondrial respiration, leading to mitochondrial bioenergy failure[43].Therefore, it can induce oxidative stress injury of the heart more selectively[29].Cardiac injury after adriamycin treatment can be clinically manifested as arrhythmia, myocardial infarction, and heart failure.Pathologically, myocardial cells are significantly reduced, mitochondria are swollen, and the expression of manganese superoxide dismutase?2 (SOD2) is significantly reduced in myocardial cells on the 14th day after adriamycin treatment[44-46].

In addition to doxorubicin, alkylating agents (cyclophosphamide),platinum compounds (cisplatin), anti?metabolic and anti?tumor drugs (fluorouracil), and even new molecular targeted drugs(trastuzumab) can all cause mitochondrial dysfunction to varying degrees and inhibit antioxidant protein (SOD)[42].Although the combination of novel molecular targeted anti?tumor drugs and multiple chemotherapy drugs has achieved remarkable results in the control of tumor progression, the combination of different anti?tumor drugs will aggravate the deterioration of cardiac function based on the cardiotoxicity of the drugs themselves.Adriamycin because of the above factors, and a new molecular targeted anti?tumor drugs in clinical application is limited by different degree, unable to complete the required course, cause cancer metastasis and recurrence rate is increased, due to the damage to the target tissue, cancer survivors in the late life quality is not guaranteed, at the same time to cancer family and social cause greater economic burden.Currently,there are no specific treatment and prevention methods for the cardiotoxicity of antitumor drugs[47].Since the damage mechanism of anti?tumor drugs is mainly to inhibit mitochondrial function and the expression of antioxidant enzymes, resulting in oxidative stress injury of myocardium, maintaining the balance between oxidants and antioxidants is one of the most promising research directions.

Previous studies have shown that Asprosin has a unique protective effect on myocardium and may play a role in the treatment of diabetic cardiomyopathy and coronary heart disease.Therefore, it is feasible to prevent cardiotoxicity caused by chemotherapeutic drugs.In the following, the protective effect of Asprosin on myocardium and the application prospect of Asprosin in the treatment of cardio?related diseases will be elaborated in detail in combination with the related pathogenesis of diabetic cardiomyopathy, ischemia reperfusion injury and cardiotoxicity caused by chemotherapeutic drugs mentioned above.

4.Protective effect and application prospect of Asprosin on myocardium

4.1 Asprosin can better remove intracellular reactive oxygen species

Under pathological conditions (high glucose stimulation, ischemia reperfusion and chemotherapy), mitochondrial function is impaired and the production of reactive oxygen species in cardiomyocytes is significantly increased, resulting in imbalance between intracellular oxidants and antioxidants and increased oxidative stress injury in myocardium.Therefore, antioxidant therapy and restriction of reactive oxygen production may be one of the effective strategies to reduce oxidative stress.

Preliminary clinical studies have shown that a variety of antioxidants, such as vitamin C, vitamin E and recombinant superoxide dismutase, fail to achieve the expected cardioprotective effect, possibly because the above antioxidants cannot reach the site related to free radical generation, namely the mitochondrial inner membrane, and cannot achieve the removal of intracellular reactive oxygen species [48-50].In animal models, mice with SOD knockout are more vulnerable to reperfusion injury, and high SOD expression has a protective effect on reperfusion injury[49].Current studies have shown that mitochondrial targeting peptides can specifically aggregate in the mitochondrial intima and have the ability to up?regulate the expression of SOD and clear H2O2 and OH·in mitochondria, thereby inhibiting mitochondrial swelling, oxidative cell death and ischemia reperfusion injury[49, 51].Since the electron respiratory chain on the mitochondrial intima is the main source of intracellular reactive oxygen species, mitochondrial targeted antioxidant peptides have the property of crossing the cell membrane and reaching the mitochondrial intima, which is very effective against oxidative stress?induced apoptosis[51].

Therefore, it is reasonable to infer that the factors that improve the antioxidant in mitochondrial intima can better reduce the production of reactive oxygen species, protect mitochondrial function and prevent oxidative stress injury.Asprosin not only up?regulated the expression of SOD2, but also improved the function of mitochondria.Therefore, it has a strong ability to remove intracellular reactive oxygen species.

4.1.1 Asprosin up?regulates the expression of SOD2

There are many different forms of antioxidants in the human body,and the most effective enzyme antioxidant is superoxide dismutase[40].This enzyme exists in three forms in the human body: copper and zinc superoxide dismutase in cytoplasm, manganese superoxide dismutase (SOD2) in mitochondria, and superoxide dismutase outside the cell [52].Manganese superoxide dismutase (SOD2),an important antioxidant enzyme that removes mitochondrial reactive oxygen species, is highly expressed in the myocardium and is localized in the mitochondrial intima.Upregulation of SOD2 expression can reduce mitochondrial oxidative damage[45].Previous studies have shown that mitochondrial targeted antioxidants (coenzyme Q10, Mito?Tempo, and peroxiredoxin?3)have achieved significant effects in the antioxidant therapy of diabetic cardiomyopathy[37].Zhang et al.[53] pointed out that Asprosin pretreated mesenchymal stem cells have strong resistance to oxidative stress stimulation in vitro and myocardial ischemia?induced apoptosis/death of cardiomyocytes in vivo.The reason is that Asprosin up?regulates antioxidant protein SOD2 and reduces the production of mitochondrial reactive oxygen species, thereby inhibiting apoptosis/death.

In CHD, the decreased SOD2 encoding gene and SOD activity are significantly correlated with the progression of CHD stenosis[54].Interestingly, another study showed that Asprosin increased 24 h after coronary angiography in patients with unstable angina pectoris compared with that on admission, and was significantly positively correlated with SYNTAX score, which was correlated with the severity of unstable angina pectoris and may be a predictor of the severity of unstable angina pectoris[55].However, it is not clear whether the elevation of Asprosin is a result of the disease itself or a reactive protective mechanism.

4.1.2 Asprosin enhances mitochondrial respiration

As mentioned above, mitochondrial functional status is a major determinant of oxidative stress damage to the myocardium.A 5?year prospective study involving 50 patients with dilated cardiomyopathy showed that the 5?year incidence of adverse cardiovascular events was low in patients with elevated Asprosin.Further studies have shown that Asprosin can protect the myocardium from hypoxia injury by enhancing mitochondrial proton leakage and mitochondrial respiration[56].However, whether Asprosin can improve mitochondrial function by affecting mitochondrial electron transport chain, mitochondrial dynamics and biogenesis needs to be further discussed in future studies.

4.2 Research prospects of Asprosin in myocardial antioxidant therapy

In coronary heart disease, mitochondrial targeted antioxidant peptide combined with mitochondrial therapy can significantly reduce ischemia reperfusion injury[54].Deacetylases (Sirtuins) that enhance mitochondrial function and up?regulate SOD2 protein expression have also been shown to be effective in chemotherapy?induced cardiotoxicity[41].All the above studies showed that increasing the mitochondrial intimal antioxidant enzyme (SOD2)and simultaneously improving mitochondrial function could better protect cardiomyocytes from oxidative stress injury.

Asprosin not only has the ability to up?regulate SOD2 expression,but also can enhance mitochondrial function, which has dual protective effects on myocardium.In addition, Asprosin can also inhibit oxidative stress injury of myocardial microvascular endothelial cells, increase the integrity and smoothness of cardiac microvascular endothelial cells, and improve cardiac function in patients with type 2 diabetes[57].

Due to metabolic disease, myocardial injury caused by ischemia?reperfusion, with myocardial injury caused by drugs have similarities, all can cause oxidative stress, leading to increased mitochondrial ros, mitochondrial dysfunction and reduced antioxidant content in cells, cell function change or loss, and Asprosin can reverse the above changes.In addition, Asprosin can also protect the endothelial cells of myocardium microvessels, so it has great research value and therapeutic potential in the treatment of heart?related diseases.

In conclusion, Asprosin is a newly discovered protein hormone,which is positively correlated with metabolic diseases (obesity, type 2 diabetes) and related metabolic parameters (BMI, HOMA?IR,etc.).It is expected to play a therapeutic potential in diseases such as anorexia and cachexia due to its role in increasing blood glucose and maintaining blood glucose balance in the body.In addition, Asprosin is involved in the regulation of myocardial oxidative stress injury caused by multiple factors, such as hyperglycemic stimulation,ischemia reperfusion and anti?tumor drugs.By enhancing mitochondrial respiration and upregulating SOD2 expression, it has a dual protective effect on myocardium and prevents myocardium from oxidative stress injury.Therefore, it has a broad research prospect in antitumor drugs and myocardial injury caused by ischemia/reperfusion.