RESUMO
According to the pathophysiological mechanisms linking particulate matter (PM2.5) exposure and cardiovascular diseases, PM2.5 may directly translocate into the blood stream and remote target organs and thereby induce cardiovascular effects. The toxicity of PM2.5 is known to induce oxidative stress in pulmonary tissue, but its impact on the redox state in heart (distant organ) is unknown and how it modulates the cardiac response to ischemia reperfusion (IR) remains unclear. In the present study, we evaluated the toxic effect of PM2.5 on cardiac physiology in the presence and absence of IR after introducing PM2.5 into the blood. Female Wistar rats were injected with diesel particulate matter (DPM) via i.p & i.v routes at a concentration of 10 µg/ml. The toxic impact of PM2.5 not only adversely affects the cardiac ultra-structure (leading to nuclear infiltration, edema, irregularities in heart muscle and nuclear infiltration), but also altered the cellular redox balance, elevated inflammation and promoted the upregulation of proapoptotic mediator genes at the basal level of myocardium. The results showed alterations in cardiac ultrastructure, elevated oxidative stress and significant redox imbalance, increased inflammation and proapoptotic mediators at the basal level of myocardium. Moreover, the cardioprotective pro survival signaling axis was declined along with an increased NF-kB activation at the basal level. IR inflicted further injury with deterioration of cardiac hemodynamic indices (Heart rate [HR], Left ventricular developed pressure [LVDP], Left ventricular end-diastolic pressure [LVEDP] and rate pressure product [RPP]) along with prominent inactivation of signaling pathways. Furthermore, the levels of GSH/GSSG, NADH/NAD, NADPH/NADP were significantly low along with increased lipid peroxidation in mitochondria of PM2.5 treated IR rat hearts. This observation was supported by downregulation of glutaredoxin and peroxiredoxin genes in the myocardium. Similarly the presence of oxidative stress inducing metals was found at a higher concentration in cardiac mitochondria. Thus, the toxic impact of PM2.5 in heart augment the IR associated pathological changes by altering the physiological response, initiating cellular metabolic alterations in mitochondria and modifying the signaling molecules.
Assuntos
Mitocôndrias Cardíacas , Traumatismo por Reperfusão Miocárdica , Material Particulado , Transdução de Sinais , Animais , Feminino , Ratos , Mitocôndrias Cardíacas/metabolismo , Mitocôndrias Cardíacas/efeitos dos fármacos , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Miocárdio/metabolismo , Miocárdio/patologia , NF-kappa B/metabolismo , Oxirredução/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Material Particulado/toxicidade , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismoRESUMO
Exposure to PM2.5 is widely acknowledged to induce cardiotoxic effects, leading to decreased myocardial tolerance to revascularization procedures and subsequent ischemia reperfusion injury (IR). However, the temporal relationship between PM2.5 exposure and vulnerability to IR, along with the underlying mechanisms, remains unclear and is the focus of this study. Female Wistar rats were exposed to PM2.5 at a concentration of 250 µg/m³ for 3 h daily over varying durations (7, 14, and 21 days), followed by IR induction. Our results demonstrated a significant increase in cardiac injury, as evidenced by increased infarct size and elevated cardiac injury markers, starting from day 14 of PM2.5 exposure, accompanied by declined cardiac function. These adverse effects were associated with apoptosis and impaired mitochondrial function, including reduced bioenergetics, mitochondrial DNA copy number and quality control mechanisms, along with inactivation of the PI3K/AKT/AMPK signalling pathways. Furthermore, analysis of myocardial tissue revealed elevated metal accumulation, particularly within mitochondria. Chelation of PM2.5 -associated metals using EDTA significantly mitigated the toxic effects on cardiac IR pathology, as confirmed in both rat myocardium and H9c2 cells. These findings suggest that metals in PM2.5 play a crucial role in inducing cardiotoxicity, impairing myocardial resilience to stress through mitochondrial accumulation and dysfunction.
Assuntos
Poluentes Atmosféricos , Traumatismo por Reperfusão Miocárdica , Material Particulado , Ratos Wistar , Animais , Traumatismo por Reperfusão Miocárdica/metabolismo , Material Particulado/toxicidade , Ratos , Feminino , Poluentes Atmosféricos/toxicidade , Metais/toxicidade , Exposição por Inalação/efeitos adversos , Apoptose/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Miocárdio/metabolismoRESUMO
Background: Renal dysfunction is known to cause heart failure. However, renal dysfunction associated with kidney surgeries (mediated by reperfusion injury) that affects the cardiac physiological function, especially during the recovery and repair phase of renal surgery is unknown. Method: Male Wistar rats (238 ± 18 g) were subjected to renal sham and ischemia-reperfusion (IR-bilateral clamping for 15 min/45 min and reperfusion for 24 h/48 h/7 days) surgeries. At the end of the experiment, the heart was isolated from the animal (to exclude neurohormonal influence) and perfused for 60 min with Krebs-Hanseleit buffer to study the physiological changes. Result: Renal artery bilateral occlusion for 45 min that creates ischemia, followed by 24 h of reperfusion did not impart any significant cardiac physiological functional decline but 48 h of reperfusion exhibited a significant decline in cardiac hemodynamic indices (Rate pressure product in x104 mmHg*beats/min: Sham- 3.53 ± 0.19, I45_R48-2.82 ± 0.21) with mild tissue injury. However, 7 days of reperfusion inflict significant physiological decline (Rate pressure product in x104 mmHg*beats/min - 2.5 ± 0.14) and tissue injury (Injury score- 4 ± 1.5) in isolated rat hearts. Interestingly, when the renal artery bilateral occlusion time was reduced to 15 min the changes in the hearts were negligible after 7 days. Cellular level exploration reveals a positive relation between functional deterioration of mitochondria and elevated mitochondrial oxidative stress and inflammation with cardiac physiological decline and injury linked with renal ischemia-reperfusion surgery. Conclusion: Cardiac functional decline associated with renal surgery is manifested during renal repair or recovery. This decline depends on cardiac mitochondrial health, which is negatively influenced by the renal IR mediators and kidney function.
RESUMO
DNA methylation plays a crucial role in the pathogenesis of myocardial ischemia reperfusion injury(I/R) and the I/R injury can be combated effectively by ischemia preconditioning (IPC), but the role is DNA methylation in this process is unknown. In this study, we uncovered the role of ischemic preconditioning (IPC)- mediated cardioprotection of rat myocardium by using a Langendorff rat heart model with 30 min of ischemia followed by 60 min of reperfusion. Heart conditioned with short cycles of ischemia and reperfusion (IPC procedure) prior to I/R protocol significantly reduced the I/R-induced global DNA hypermethylation level by 32% and the DNMT activity by 33% while rendering cardioprotection. Blocking the PI3K pathway via wortmannin not only negates the cardio-protection by IPC, but also increases the methylation of DNA by 75%. Besides, the correlation analysis showed a negative relationship between PI3K gene expression and the global DNA methylation level (r = - 0.8690, p = 0.0419) in IPC-treated rat hearts. Moreover, the global level DNA hypomethylation induced by IPC exhibited a regulatory effect on the genes involved in I/R pathology mediators like apoptosis (Caspase3), mitochondrial function (PGC 1α, TFAM, ND1) and oxidative stress (CuZnSOD, SOD2), and their corresponding function. The present study results provide novel evidence for the involvement of DNA methylation in the IPC procedure, and suggest DNA methylation as one of the potential therapeutic targets regulated by ischemic preconditioning in rat hearts subjected to ischemia reperfusion. Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-024-03965-0.
RESUMO
Calcium oxalate urolithiasis is one of the most common urinary tract diseases and is of high prevalence. The present study proposes to evaluate the antilithiatic property of hydrogen sulfide and its metabolites like thiosulfate & sulfate in an in vitro model.
The antilithiatic activity of sodium hydrogen sulfide (NaSH), sodium thiosulfate (Na2S2O3) and sodium sulfate (Na2SO4) on the kinetics of calcium oxalate crystal formation was investigated both in physiological buffer and in urine from normal and recurrent stone forming volunteers. The stones were characterized by optical and spectroscopic techniques.
The stones were characterized to be monoclinic, prismatic and bipyramidal habit which is of calcium monohydrate and dihydrate nature. The FTIR displayed fingerprint corresponding to calcium oxalate in the control while in NaSH treated, S=O vibrations were visible in the spectrum. The order of percentage inhibition was NaSH>Na2S2O3>Na2SO4.
Our study indicates that sodium hydrogen sulfide and its metabolite thiosulfate are inhibitors of calcium oxalate stone agglomeration which makes them unstable both in physiological buffer and in urine. This effect is attributed to pH changes and complexing of calcium by S2O32-and SO42- moiety produced by the test compounds.