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Consequential Impact of Particulate Matter Linked Inter-Fibrillar Mitochondrial Dysfunction in Rat Myocardium Subjected to Ischemia Reperfusion Injury

ABSTRACT:

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Inhalation of particulate matter (PM2.5) is known to cause cardiac effects and exacerbate any pre-existing cardiac diseases. However, the severity of toxicity depends on how much PM2.5 has reached the blood circulation and then finally the heart. The consequential impact of PM2.5 on the heart depends on its potential to alter cardiac oxidative stress and mitochondrial function that in turn controls the contractile function of the heart. In fact, this effect is partly concentration dependent. In the present study, we demonstrated that blood borne PM2.5 can inflict cardiac injury and compromise physiological response. Moreover, the results from our study show that cardiac tolerance to resist ischemia reperfusion injury (IR) is low in PM2.5 administered rat hearts. Cellular level analysis of the data suggests that PM2.5 gets deposited in the mitochondria which in turn increases the oxidative stress by disturbing redox couple and inducing mitochondrial dysfunction. In fact, the higher pathological changes occur with the direct entry of PM into the myocardium.

Abstract

A previous study has reported that exposure to PM2.5 from diesel exhaust (diesel particulate matter (DPM)) for 21 days can deteriorate the cardiac recovery from myocardial ischemia reperfusion injury (IR), where the latter is facilitated by the efficiency of mitochondrial subpopulations. Many investigators have demonstrated that IR impact on cardiac mitochondrial subpopulations is distinct. In the present study, we decipher the role of PM2.5 on IR associated mitochondrial dysfunction at the subpopulation level by administrating PM2.5 directly to isolated female rat hearts via KH buffer. Our results demonstrated that PM2.5 administered heart (PM_C) severely deteriorated ETC enzyme activity (NQR, SQR, QCR, and COX) and ATP level in both IFM and SSM from the normal control. Comparatively, the declined activity was prominent in IFM fraction. Moreover, in the presence of IR (PM_IR), mitochondrial oxidative stress was higher in both subpopulations from the normal, where the IFM fraction of mitochondria experienced elevated oxidative stress than SSM. Furthermore, we assessed the in vitro protein translation capacity of IFM and SSM and found a declined ability in both subpopulations where the inability of IFM was significant in both PM_C and PM_IR groups. In support of these results, the expression of mitochondrial genes involved in fission, fusion, and mitophagy events along with the DNA maintenance genes such as GUF1, LRPPRC, and HSD17-b10 were significantly altered from the control. Based on the above results, we conclude that PM2.5 administration to the heart inflicted mitochondrial damage especially to the IFM fraction, that not only deteriorated the cardiac physiology but also reduced its ability to resist IR injury.

SUBMITTER: Sivakumar B

PROVIDER: S-EPMC9775305 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

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Project description:BackgroundSevoflurane postconditioning (SevP) effectively relieves myocardial ischemia/reperfusion (I/R) injury but performs poorly in the diabetic myocardium. Previous studies have revealed the important role of increased oxidative stress in diabetic tissues. Notably, mitochondrial fission mediated by dynamin-related protein 1 (Drp1) is an upstream pathway of reactive oxygen production. Whether the ineffectiveness of SevP in the diabetic myocardium is related to Drp1-dependent mitochondrial fission remains unknown. This study aimed to explore the important role of Drp1 in the diabetic myocardium and investigate whether Drp1 inhibition could restore the cardioprotective effect of SevP.MethodsIn the first part of the study, adult male Sprague-Dawley rats were divided into 6 groups. Rats in the diabetic groups were fed with high-fat and high-sugar diets for 8 weeks and injected intraperitoneally with streptozotocin (35 mg/kg). Myocardial I/R was induced by 30 min of occlusion of the left anterior descending branch of the coronary artery followed by 120 min of reperfusion. SevP was applied by continuous inhalation of 2.5 % sevoflurane 1 min before reperfusion, which lasted for 10 min. In the second part of the study, we applied mdivi-1 to investigate whether Drp1 inhibition could restore the cardioprotective effect of SevP in the diabetic myocardium. The myocardial infarct size, mitochondrial ultrastructure, apoptosis index, SOD activity, MDA content, and Drp1 expression were detected.ResultsTTC staining and TUNEL results showed that the myocardial infarct size and apoptosis index were increased in the diabetic myocardium. However, SevP significantly alleviated myocardial I/R injury in the normal myocardium but not in the diabetic myocardium. Additionally, we found an elevation in Drp1 expression, accompanied by more severe fission-induced structural damage and oxidative stress in the diabetic myocardium. Interestingly, we discovered that the beneficial effect of SevP was restored by mdivi-1, which significantly suppressed mitochondrial fission and oxidative stress.ConclusionsOur study demonstrates the crucial role of mitochondrial fission dependent on Drp1 in the diabetic myocardium subjected to I/R, and strongly indicates that Drp1 inhibition may restore the cardioprotective effect of SevP in diabetic rats.

Project description:ObjectiveThis study aimed to explore metabolic reprogramming in diabetic myocardium subjected to ischemia-reperfusion injury (I/RI) and potential mechanisms.BackgroundIncreased vulnerability after I/RI in diabetic myocardium is a major cause of the high prevalence of perioperative adverse cardiac events, and the specific alterations in energy metabolism after I/RI in diabetic myocardium and the impact on increased vulnerability are not fully understood.MethodsMetabolomic methods were used to explore the differences and characteristics of metabolites in the heart tissues of four groups, and then, single-cell RNA sequencing (ScRNA-seq) was used to explore the potential mechanism of metabolic reprogramming.ResultsIt was found that the fatty acid metabolism of db/db mouse I/RI (DMI) showed a significant upward trend, especially the metabolites of ultra-long and medium-long-chain fatty acids; the metabolic flow analysis found that the U-13C glucose M + 6 was significantly higher in the C57BL mouse sham operation (NM) group than in the db/db mouse sham operation (DM) group, and in the C57BL mouse I/RI (NMI) than in the DMI group. Compared with the NMI group, the intermediate metabolites of glycolysis and tricarboxylic acid (TCA) cycle were significantly reduced in the DMI group; all comparisons were statistically significant (p < 0.05), indicating that the glucose uptake of diabetic myocardetis, the ability of glucose glycolysis after I/RI, and the contribution of glucose to TCA were significantly reduced. The results of ScRNA-seq revealed that the number of Cluster 0 myocardial isoforms was significantly increased in diabetic myocardium, and the differential genes were mainly enriched in fatty acid metabolism, and the PPARA signaling pathway was found to be over-activated and involved in the regulation of metabolic reprogramming of diabetic myocardial I/RI.ConclusionMetabolic reprogramming of diabetic myocardial I/RI may be the main cause of increased myocardial vulnerability. The number of myocardial subtype Cluster 0 increased significantly, and PPARA PPARA is a ligand-activated receptor of the nuclear hormone receptor family that plays a central regulatory role in lipid metabolism. signaling pathway activation may be a potential mechanism for reprogramming metabolism in diabetic myocardium.

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Consequential Impact of Particulate Matter Linked Inter-Fibrillar Mitochondrial Dysfunction in Rat Myocardium Subjected to Ischemia Reperfusion Injury

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