Ultrafine Particulate Matter Increases Cardiac Ischemia/Reperfusion Injury via Mitochondrial Permeability Transition Pore

Abstract

Ultrafine particulate matter (UFP) has been associated with increased cardiovascular morbidity and mortality. However, the mechanisms that drive PM-associated cardiovascular disease and dysfunction remain unclear. We examined the impact of oropharyngeal aspiration of 100 μg UFP from the Chapel Hill, NC, air shed in Sprague-Dawley rats on cardiac function, arrhythmogenesis, and cardiac ischemia/reperfusion (I/R) injury using a Langendorff working heart model. We found that exposure to UFP was capable of significantly exacerbating cardiac I/R injury without changing overall cardiac function or major changes in arrhythmogenesis. Cardiac I/R injury was attenuable with administration of cyclosporin A (CsA), suggesting a role for the mitochondrial permeability transition pore (mPTP) in UFP-associated cardiovascular toxicity. Isolated cardiac mitochondria displayed decreased Ca²⁺ buffering before opening of the mPTP. These findings suggest that UFP-induced expansion of cardiac I/R injury may be a result of mPTP Ca²⁺ sensitization resulting in increased mitochondrial permeability transition and potential initiation of mPTP-associated cell death pathways.

Keywords: Cardiac; Mitochondria; Particulate matter; Reperfusion injury; mPTP.

Figure 1. Cardiac Electrical Activity

Ex vivo electrocardiogram recordings captured throughout the duration of the Langendorff protocol. Open bars represent values obtained from control hearts and solid bars represent values from age matched hearts treated with 0.2 μM CsA. Parameters measured were number of PVCs during a 10 minute baseline period (A), Time to VT/VF following reperfusion (B), and arrhythmia scoring for the 1^st hour of reperfusion (C). Statistical significance considered as p < 0.05 by two-way ANOVA with Bonferroni post-hoc test. Data are reported as mean ± SEM with n = 4–6.

Figure 2. Myocardial Ischemia/Reperfusion Injury

Following a baseline period ex vivo hearts were subjected to 20 minutes of ischemia followed by 2 hours of reperfusion. Exposure to UFP was associated with expansion of cardiac ischemia/reperfusion injury 24 hours following the oropharyngeal aspiration. Open bars represent values obtained from control hearts and Solid bars represent values from hearts treated with 0.2 μM CsA. Statistical significance considered at p < 0.05 vs saline and indicated by (*) as calculated by two-way ANOVA with Bonferroni post-hoc test. Data are reported as mean ± SEM with n = 6–7.

Figure 3. Isolated Mitochondria Ca²⁺ Sensitivity

Quantification of calcium retention capacity following 50 nmol pulses of CaCl₂ in isolated mitochondria from hearts of rats that aspirated saline or UFP 24 hours prior to their isolation. Isolated mitochondria were treated with either 0.2 μM CsA (solid bars) or control (open bars). Statistical significance at p < 0.05 vs saline indicated by (*), or vs +CsA indicated by (#), were calculated by two-way ANOVA with Bonferroni post hoc test. Data are reported as mean ± SEM with n = 3–4 experiemental groups.