Augmented coronary vascular smooth muscle response to endothelin-1 exacerbates cardiac injury following pulmonary exposure to engineered nanomaterials

Multi-walled carbon nanotubes (MWCNT) and 60-carbon fullerenes (C60) are important engineered nanoparticles (ENP) used across industry. Exposure to ENP potentially promotes cardiovascular detriments. The hypotheses that exposure to either MWCNT or C60 would exacerbate cardiac ischemia/reperfusion (I/R) injury and promote enhanced coronary artery contraction in response to endothelin-1 (ET-1) by a cyclooxygenase-mediated mechanism were tested. One day following intratracheal instillation of vehicle, 1, 10 or 100 [mu]g MWCNT in male Sprague-Dawley rats, hearts were isolated and mounted on a Langendorff perfusion apparatus. Hearts from animals exposed to 100 [mu]g MWCNT exhibited 3x more premature ventricular contractions during perfusion at baseline. Cardiac perfusion was stopped to induce ischemia for 20 minutes and then restarted to study injuries induced by I/R. Post-reperfusion myocardial infarction expanded 18% in the 100 [mu]g MWCNT group compared to the vehicle group. We also noted that post-ischemia cardiac release of ET-1 was increased 4-fold and coronary reperfusion flow was reduced 30% in the 100 [mu]g MWCNT group compared to the vehicle group. We next evaluated isolated coronary artery ET-1-mediated stress (mN/mm2) generation by wire myography, 24 hours after intratracheal instillation of 100 [mu]g MWCNT or vehicle. Coronary artery stress generation in response to ET-1 was increased 35% in the MWCNT group compared to the vehicle group and was dependent on cyclooxygenase/thromboxane signaling. Similar endpoints were examined following C60 exposure. We measured myocardial infarction following I/R in situ and coronary artery ET-1-mediated stress responses by wire myography, 24 hours after intratracheal or intravenous administration of vehicle or 28 [mu]g C60. Myocardial infarction expanded between 70% and 110% across all C60 groups. Coronary artery stress generation in response to ET-1 was elevated by 56% in the male intratracheal C60 group compared to the vehicle group and was dependent on cyclooxygenase signaling. ET-1 responses in all other C60 groups were not different than vehicle. These results support the potential for pulmonary exposure to carbon-based ENP to exacerbate cardiac I/R injury and promote dysfunction in coronary arteries associated with ET-1/cyclooxygenase axis. Our results indicate that therapeutic targeting of ET-1 or cyclooxygenase signaling might prevent cardiovascular detriments associated with ENP exposure.Ph.D