Carboxyhemoglobin Particle Infusion, but not Carbon Monoxide Inhalation ameliorates Myocardial Infarction via Attenuated Oxidative Stress and In Situ Inflammation in a Rat Model

Abstract

Objective: Effects of PEGylated-carboxyhemoglobin bovine (SG) infusion and carbon monoxide (CO) inhalation were compared in a rat model of myocardial infarction (MI). Methods: Lewis rats with induced MI received either 10 mL/kg of SG or of saline (SL), or 400 ppm CO inhalation (CO) daily for 3 days, 4 doses in total. On the fourth day, all animals had left ventricular (LV) functions studied by pressure-volume relationship analyses or in-situ myocardial gene expression by polymerase-chain reaction (PCR). Results: Both SG infusion and CO inhalation increased the arterial carboxyhemoglobin fraction to 10%, which decreased the total O2 content by 10% for 3 hours before returning to control level, except for the plasma hemoglobin (Hb) over 200 mg/dL 24 hours later, in SG rats. Four days after MI, the SL and CO rats had enhanced cardiac contraction and relaxation, while the SG rats had LV end-systolic pressure, and the isovolumic contraction as well as relaxation remained suppressed at the post-MI levels. PCR showed significant reductions in in-situ antioxidant transcriptional master regulator (Nrf2), its down-stream antioxidant response genes (Nqo-1), hypoxic signal transduction in SG compared to SL or CO rats with enhanced pro-inflammatory, pro-apoptotic genes, and myocardial damage. These cardiac indices were reversed 4 weeks after MI, when SG had less LV dilatation, dysfunction, and myoglobin loss than those with SL or CO. Conclusion: The results suggest that repeated SG infusion, but not CO inhalation, generates less oxidative stress, reduces hypoxic responses, supports early hemodynamics, and alleviates cardiac compensation early after MI, resulting in attenuated LV dilatation, dysfunction, and myoglobin loss late after MI in this rat model.