Physicochemical Properties And Molecular Mechanism Of Myocardial Structure And Functional Damage Caused By Atmospheric Fine Particles

In recent years,haze has continued to hang over most of areas of China which is seriously threatening people’s health and quality of life.The high concentration of atmospheric fine particles(PM_2.5)is directly associated to the formation of haze.Due to meteorological and human interference,there are spatial and temporal difference in distribution and diversity in sources（vehicle exhaust,factory exhaust,waste incineration,wind and sand dust,etc.）of PM_2.5.In addition,PM_2.5 which is small volume and large specific surface area can carry various types of toxic components（metal components,water-soluble components,organic components,etc.）,which can lead to long-lasting toxic effects on human body.A considerable of epidemiological studies and experiments have shown that PM_2.5 is one of established pathogenetic factor that can lead to a series of cardiovascular system diseases,such as heart ischemia,arrhythmia and heart failure.Myocardial metabolism remodeling（MMR）is an important factor in the development of heart failure.During embryonic period,the main source of myocardial energy is glycolysis.After birth,fatty acid oxidation is progressively becoming the main energy source.While,the main energy source undergoes "embryogenic" transformation when heart failure was happened.MMR as a whole process of compensatory hypertrophy and heart failure,whether PM_2.5 induced heart failure by affecting the normal use of energy substances has not been reported.Therefore,this study,on the one hand,showed the potential molecular mechanisms of myocardial injury induced by seasonal PM_2.5 from the perspective of MMR.In addition,one of the main mechanisms of PM_2.5 affecting cardiomyocyte injury is inflammation.Inflammatory factors are released by lungs and vascular endothelial cells after PM_2.5,followed by vascular damage,the promotion of coagulation and thrombosis,then the damage of myocardial.Therefore,on the other hand,this study focused on the inflammatory effects to explore the main toxic components of PM_2.5-induced heart failure,so as to provide acontent includes the following parts:1.Dose and seasonal differences in the effects of PM_2.5 exposure on cardiac structure and function in rats.Based on the actual PM_2.5 concentration in Taiyuan,myocardial function of SD rats exposed to low,medium and high doses in summer and winter were evaluated.It was found that the exposure of PM_2.5 in the high-dose group in the summer and the medium-and high-dose groups in the winter caused a decrease in cardiac contractility and heart rate,and a heart rate variability in SD rats.Therefore,the results in this section showed that high concentrations of PM_2.5 can induce the heart failure in SD rats,which reflected a seasonal difference.2.Seasonal differential effects of PM_2.5 exposure on the selection and utilization of myocardial energy substrates.In order to further explore the toxic effects of PM_2.5 at different environmental concentrations,the myocardial imparment was firstly tested by TUNEL assay.It was showed that haze dose PM_2.5 exposure would incur a toxic effect on rat myocardium,and the effect in winter were greater than that in summer.Next,in order to further explore whether MMR is a factor that causes the myocardial toxicology of PM_2.5,energy substrates and their transporters were studied in vivo and vitro.It was found that fatty acid content was reduced and glucose content was increased through the decrease in fatty acid-related transporters and the increase in glucose-related transporters after high concentrations of PM_2.5stimulation.Therefore,this section confirms that PM_2.5 can affect the energy transporters then leads to a change in energy utilization,which eventually leads to the disorders of myocardial energy synthesis.Meanwhile,winter PM_2.5 is more toxic than that in summer.3.PM_2.5 exposure mediated the transform in the utilization of energy substrates by the regulation of PPARα.The above results indicated that myocardial energy synthesis was impaired by PM_2.5 exposure through the change of energy substrates utilization.However,the related molecular mechanism is unclear.Myocardial energy metabolism is related to the expression of PPARs.Therefore,PPARs family members was then examined.It was found that there was a significant reduction on PPARα expression.Then,PPARα activator WY-14643 was adopted in H9C2 cells for 24 h.The results showed that co-treatment with WY-14643 and winter PM_2.5contributed to the recovery of PPARα expression in H9C2 cells,compared with PM_2.5 treatment alone.Therefore,this section confirms that PPARα is a main regulator in the PM_2.5-induced alteration of cardiac energy substrates transport.4.Toxic component of PM_2.5 on myocardial survival and inflammatory damage effects.Considering the complexity of the PM_2.5 component,the main toxic components causing heart failure is unclear.Therefore,in this section,the survival and inflammatory in H9C2 cells after PM_2.5 exposure for24 h and 48 h were selected to explore the key components of PM_2.5-induced toxic damage to the myocardium.The results showed that the different components had no significant effect on the survival rate of H9C2 cells under the specific environmental proportion.After exposure to different components of PM_2.5 in winter at the same concentration,the survival rate of H9C2 cells was composite group > organic group > metal group >water-soluble group.Regarding the inflammatory effects,winter PM_2.5exposure induced myocardial inflammatory damage by activating the inflammatory factors TNF-α and IL-1β.At the same concentration,the effect order was metal group > organic group > component group > water-soluble group.In summary,this study demonstrated that seasonal PM_2.5 exposure caused the disorder of ATP generation through the regulation of PPARα-mediated selection and utilization of energy substrates and their transporters.The effect of PM_2.5 in winter was more serious than in summer.The components of PM_2.5 that cause myocardial cell survival toxicity and inflammatory damage may be organic and metal components.But the inflammatory to these two components is significantly different.This study contributes in a better understanding on haze-induced cardiovascular disease by revealing crucial indicators involved in this phenomenon.