Effects Of PM_2.5 On Hospital Admissions For Cardiovascular Disease In Lanzhou Urban Area And The Mechanisms Of Damage To Cardiomyocyte

Background:According to the 2019 China Health Statistical Yearbook,cardiovascular disease（including heart disease and cerebrovascular disease,CVD）ranks first among the major diseases and causes of death among residents since 2005,and continues to grow rapidly.According to the data of China Cardiovascular Health and Disease Report 2019,it is estimated that there are 330 million CVD patients in China,including 13 million stroke,11 million coronary heart disease and 8.9 million heart failure.CVD is causing an increasing economic and social burden.In addition to the traditional risk factors,such as hypertension,dyslipidemia,diabetes,etc.,air pollution is listed as the seventh risk factor for CVD.Among the air pollutants,fine particulate matter(PM_2.5)have the greatest impact on health.Because of its small size and light weight,PM_2.5 can carry toxic substances into the deep respiratory tract,deposit in the terminal bronchioles and alveoli,and even break through the pulmonary capillary barrier into the blood circulatory system.The inflammation and oxidative stress caused by PM_2.5 damages to many systems,especially the cardiovascular system.Studies have shown that the cardiovascular system surpasses the respiratory system to become the most important target organ of PM_2.5.It is reported that short-term exposure to PM_2.5 can cause acute cardiovascular events.However,most of the previous studies to evaluate the effects of PM_2.5 on CVD have been conducted in Europe and North America,and the evidence from developing countries in Asia is still limited,while there are few studies in Northwest China.In addition,the mechanism of cardiovascular injury caused by PM_2.5 is still unclear.At present,the research on the mechanism of cardiomyocyte injury caused by PM_2.5 is mainly focused on the relationship between PM_2.5 exposure and cardiomyocyte apoptosis.However,apoptosis is not the only regulatory form of cell death,a large proportion of cell death is programmed cell necrosis caused by active regulation,and like apoptosis,programmed cardiomyocyte necrosis is also an important part of the mechanism of cardiac function injury.However,there are few reports related to programmed cardiomyocyte necrosis in cardiomyocyte injury induced by PM_2.5.At the same time,more and more evidence shows that inflammation caused by PM_2.5 exposure is the main driving force for the development of cardiovascular disease;some studies have shown that myocardial NLRP3 inflammasome activation induced by PM_2.5 exposure plays a key role in myocardial injury,but the specific mechanism of NLRP3inflammasome activation induced by PM_2.5 is not clear.Objective:1.To study the effect of short-term exposure to air PM_2.5 on CVD admission of residents in the urban area of Lanzhou.2.To explore the programmed cardiomyocyte necrosis induced by PM_2.5 through mitochondrial injury and promoting cardiac function injury in HFp EF mice.3.To explore the effect of PM_2.5 on Mitochondrial reactive oxygen species（mt ROS）/Thioredoxin-interacting protein（TXNIP）/NOD-like receptor（NLR）family pyrin domain-containing 3（NLRP3）signaling pathway.Methods:1.The CVD hospital admission data from three large general hospitals,air pollutants and meteorological data in the urban area of Lanzhou from 2014 to 2019were collected.The relationship,lag effect and cumulative lag effect between PM_2.5concentration and total CVD,ischemic heart disease（IHD）,arrhythmia（HRD）,heart failure（HF）and cerebrovascular disease（CD）were analyzed by distributed lag nonlinear model（DLNM）based on Poisson distribution.At the same time,the total CVD and different types of CVD patients were stratified according to sex and age,in order to further study the effect of PM_2.5 pollution on CVD hospital admission of different gender and age.In addition,the above method was used to study the difference of harmful effects of short-term exposure of PM_2.5 on CVD admission of residents in Lanzhou urban area in cold season and warm season.（Part I）2.HFp EF model mice were exposed to concentrated ambient PM_2.5（CAP）or filtered air（FA）for 6 weeks.The changes of myocardial pathology and cardiac function of HFp EF mice in CAP group and FA group were compared.The oxidative stress,cell necrosis and mitochondrial permeability transition pore（m PTP）kinetics of H9C2 cells induced by PM_2.5 exposure,and the changes of mitochondrial function and real-time ATP production rate of i PSC-CMs cells induced by PM_2.5 exposure were detected in vitro.（Part II）3.c57BL6 mice were exposed to CAP or FA for 6 weeks,the myocardial pathological changes and cardiac function changes of the two groups were compared,and then transcriptome sequencing and analysis of myocardial tissue was conducted to verify the role of mt ROS/TXNIP/NLRP3 signal pathway in PM_2.5-induced myocardial inflammatory injury.（Part III）Results:1.The results of epidemiological study showed that when the air PM_2.5concentration increased by 10μg/m³,the relative risk of daily admission of total CVD and different types of CVD increased,but the lag or cumulative lag of the maximum effect was different in each type of CVD.In addition,although there was no significant difference in the gender and age stratified harmful effects of PM_2.5 on total CVD,IHD,HRD,HF and CD hospital admissions,the RR values of total CVD and all types of CVD exposed to PM_2.5 were always higher in male than in female,and higher in patients≥65 years old than in patients<65 years old.In the cold season,the harmful effects of PM_2.5 on total CVD,IHD,HRD and HF admissions were statistically significant,but the harmful effects on CD admission were not statistically significant;in the warm season,the RR values of PM_2.5 on total CVD and different types of CVD admissions were not statistically significant.（Part I）2.The results of animal experiments showed that exposure to CAP could promote mitochondrial damage,DNA oxidative damage in myocardial nuclei,myocardial inflammation,fibrosis and cardiac function damage in HFp EF model mice,in addition,p53 and cyclophilin D（Cyp D）expression increased in HFp EF model mice exposed to CAP and there was interaction between them.The results of cell experiment showed that PM_2.5 could cause the increase of reactive oxygen species,the oxidative damage of DNA,the decrease of mitochondrial membrane potential and the opening of m PTP,accompanied by mitochondrial dysfunction and the decrease of Mitochondrial oxidative phosphorylation-related ATP（Mito ATP）production rate,and finally increased cardiomyocytes necrosis.Cpy D inhibitor cyclosporine A（Cs A）can effectively reverse the decrease of mitochondrial membrane potential and H9C2 cell death induced by PM_2.5.（Part II）3.The results of animal experiments also showed that exposure to CAP could also cause mitochondrial damage,myocardial inflammation,fibrosis and cardiac function damage in c57BL6 mice.At the same time,exposure to CAP increased myocardial mitochondrial ROS（mt ROS）,up-regulated TXNIP expression and activated NLRP3 inflammasome in c57BL6 mice.（Part III）Conclusions:1.Short-term PM_2.5 exposure can increase the risk of CVD hospital admissions in the urban population of Lanzhou,and the maximum effect of lag days or cumulative lag days vary with different type of CVD diseases.2.PM_2.5 can lead to programmed cardiomyocyte necrosis by inducing the opening of m PTP,and then cause cardiac function injury in HFp EF mice.3.PM_2.5 induced mitochondrial damage,increased mt ROS production and up-regulated TXNIP expression,which may be the key mechanism leading to NLRP3inflammasome activation and myocardial inflammatory injury in c57BL6 mice.