Acute myocardial infarction in streptozotocin-induced hyperglycaemic rats: protection by a carbon monoxide-releasing molecule (CORM-3)

Abstract

Here, we have studied the effects of a carbon monoxide-releasing molecule (CORM-3, tricarbonylchloro(glycinato)ruthenium(II)) on acute myocardial ischemia/reperfusion (I/R) injury in hyperglycaemic streptozotocin-treated rats (STZ rats). Occlusion of the left descending coronary artery for 25 min followed by a 2-h reperfusion in STZ-induced hyperglycaemic rats was used as the model. CORM-3 and its inactive counterpart (iCORM-3) were administered 1 h prior to ischemia. The parameters measured included myocardial infarct size (IS) and a selection of inflammatory, oxidative markers and endothelial progenitor cells (CD34⁺ and CD117/c-kit⁺. In STZ-induced hyperglycaemic rats, occlusion of the left descending coronary artery caused injury of the myocardial tissue with an IS of ~70%, expressed as fraction of the area at risk. Given intraperitoneally 1 h prior to ischemia, CORM-3 (2-8 mg/kg) afforded significant dose-dependent cardio-protection. Specifically, pre-treatment with CORM-3 reduced infarct size by 14 ± 0.6%, 34 ± 1% and 53 ± 1.6% for doses of 2, 4 and 8 mg/kg, respectively. A negative control (iCORM-3) failed to prevent the cardiac damage induced by I/R. CORM-3 pre-treatment augmented cardiac heme oxygenase-1 (HO-1) protein levels and was associated with an increased number of CD34⁺- and CD117/c-kit⁺-positive immunostaining. Modulation of these markers was associated with augmented cardiac eNOS expression and levels of the cytokines TNF-α and IL-1 beta. CORM-3 afforded significant cardio-protection against acute myocardial infarction in STZ-induced hyperglycaemic rats through liberation of small amounts of CO. Of interest, CORM-3 promoted recruitment of the endogenous endothelial progenitor cells within the myocardium, possibly through modulation of cardiac HO-1 and eNOS expression and/or function.

Heme Oxygenase-1 Induction by Carbon Monoxide Releasing Molecule-3 Suppresses Interleukin-1β-Mediated Neuroinflammation

“…The present results are consistent with reports indicating that upregulation of HO-1 transcription is mediated by either induction of c-Jun and c-Fos, or by AP-1 activity in various cell types (Kiemer et al, 2003 ; Cheng et al, 2006 ; Hsieh et al, 2010 ). Furthermore, upregulation of HO-1 protected against IL-1β-induced cell migration, via inhibition of MMP-9 activity in RBA-1 cells, which is consistent with evidence for endogenous endothelial progenitor cell recruitment in myocardium of hyperglycemic streptozotocin-treated rats (Filippo et al, 2012 ).…”

Telmisartan cardioprotects from the ischaemic/hypoxic damage through a miR‐1‐dependent pathway

“…Rats were kept under artificial ventilation with room air at a rate of 56 strokes/min, a stroke volume of 1.0‐1.5 mL/100 g and a positive‐end expiratory pressure of 0.5‐1 cm H 2 O. Overall mortality was <5% throughout the entire study, in line with the usual procedures in our laboratory …”

“…Overall mortality was <5% throughout the entire study, in line with the usual procedures in our laboratory. 21…”

Cardiac Progenitor Cells and the Interplay with Their Microenvironment

“…A number of studies have verified the presence of c-kit + cells in hypertrophic adult human hearts [ 12 ], after myocardial infarction [ 6 , 50 , 53 , 63 ] and after ischemia/reperfusion injury [ 64 , 65 ]. In chronic heart failure, both increases and decreases in cell numbers have been described [ 6 , 66 , 67 ].…”