Freddy G. Ganse

Air pollution, particularly particulate matter (PM), is a major contributor to cardiovascular morbidity and mortality. We previously showed that diesel exhaust particles (DEPs) exposure increases arrhythmia susceptibility in rats, associated with myocardial oxidative stress and inflammation. However, the impact of DEPs on myocardial metabolism remains incompletely characterized. Here we aim to investigate whether DEP exposure induces time-dependent alterations in cardiac and plasma metabolic profiles following short- and longer-term intratracheal instillations in rats. Sprague–Dawley rats received intratracheal instillations of DEPs or saline three times weekly for one or three weeks. Myocardial and plasma metabolites were analyzed by ¹H nuclear magnetic resonance spectroscopy, followed by discriminant and pathway analyses. Myocardial metabolomic profiling proved supportive of group separation, particularly one week after exposure. Seventeen of 22 metabolites were significantly altered. One week of DEP exposure reduced succinate, acetate, formate, 3-hydroxybutyrate, ATP, and ADP levels, a pattern consistent with alterations in mitochondrial oxidative metabolism and β-oxidation. Increased glucose and lactate levels were consistent with a greater reliance on glycolytic metabolism. Amino acid accumulation, along with increased inosine, pointed towards altered amino acid utilization and enhanced nucleotide degradation. Pathway analyses identified purine metabolism, glycolysis, citrate cycle, and pyruvate metabolism as some of the affected pathways, with enrichment of the citric acid cycle and mitochondrial electron transport chain. Most alterations resolved after three weeks. In contrast, changes in plasma were modest. In conclusion, DEP exposure induces transient metabolic remodeling in the myocardium, characterized by alterations consistent with reduced oxidative metabolism, increased glycolytic reliance, and disruption of energy and redox homeostasis, providing mechanistic insight into pollution-induced cardiac dysfunction.

Succinate dehydrogenase inhibition with malonate during initial reperfusion reduces myocardial infarct size in both isolated mouse hearts subjected to global ischemia and in in situ pig hearts subjected to transient coronary ligature. However, the long-term effects of acute malonate treatment are unknown. Here, we investigated whether the protective effects of succinate dehydrogenase inhibition extend to a reduction in scar size and adverse left ventricular remodeling 28 days after myocardial infarction. Initially, ten wild-type mice were subjected to 45 min of left anterior descending coronary artery (LAD) occlusion, followed by 24 h of reperfusion, and were infused during the first 15 min of reperfusion with saline with or without disodium malonate (10 mg/kg/min, 120 μL/kg/min). Malonate-treated mice depicted a significant reduction in infarct size (15.47 ± 3.40% of area at risk vs. 29.34 ± 4.44% in control animals, p < 0.05), assessed using triphenyltetrazolium chloride. Additional animals were then subjected to a 45 min LAD ligature, followed by 28 days of reperfusion. Treatment with a single dose of malonate during the first 15 min of reperfusion induced a significant reduction in scar area, measured using Picrosirius Red staining (11.94 ± 1.70% of left ventricular area (n = 5) vs. 23.25 ± 2.67% (n = 9), p < 0.05), an effect associated with improved ejection fraction 28 days after infarction, as determined using echocardiography, and an attenuated enhancement in expression of the pro-inflammatory and fibrotic markers NF-κB and Smad2/3 in remote myocardium. In conclusion, a reversible inhibition of succinate dehydrogenase with a single dose of malonate at the onset of reperfusion has long-term protective effects in mice subjected to transient coronary occlusion.