Cardioprotective Actions by a Water-Soluble Carbon Monoxide–Releasing Molecule

Abstract

Abstract-Carbon monoxide, which is generated in mammals during the degradation of heme by the enzyme heme oxygenase, is an important signaling mediator. Transition metal carbonyls have been recently shown to function as carbon monoxide-releasing molecules (CO-RMs) and to elicit distinct pharmacological activities in biological systems.In the present study, we report that a water-soluble form of CO-RM promotes cardioprotection in vitro and in vivo. Specifically, we found that tricarbonylchloro(glycinato)ruthenium(II) (CORM-3) is stable in water at acidic pH but in physiological buffers rapidly liberates CO in solution. Cardiac cells pretreated with CORM-3 (10 to 50 mol/L) become more resistant to the damage caused by hypoxia-reoxygenation and oxidative stress. In addition, isolated hearts reperfused in the presence of CORM-3 (10 mol/L) after an ischemic event displayed a significant recovery in myocardial performance and a marked and significant reduction in cardiac muscle damage and infarct size. The cardioprotective effects mediated by CORM-3 in cardiac cells and isolated hearts were totally abolished by 5-hydroxydecanoic acid, an inhibitor of mitochondrial ATP-dependent potassium channels. Predictably, cardioprotection is lost when CORM-3 is replaced by an inactive form (iCORM-3) that is incapable of liberating CO. Using a model of cardiac allograft rejection in mice, we also found that treatment of recipients with CORM-3 but not iCORM-3 considerably prolonged the survival rate of transplanted hearts. These data corroborate the notion that transition metal carbonyls could be used as carriers to deliver CO and highlight the bioactivity and potential therapeutic features of CO-RMs in the mitigation of cardiac dysfunction. Key Words: transition metal carbonyls Ⅲ carbon monoxide-releasing molecules Ⅲ myocardial ischemia Ⅲ heart transplantation Ⅲ reperfusion injury M ammalian cells constantly generate carbon monoxide (CO) gas via the endogenous degradation of heme by a family of constitutive (HO-2) and inducible (HO-1) heme oxygenase enzymes. 1,2 Firstly described as a putative neural messenger, 3 CO is now regarded as a versatile signaling molecule having essential regulatory roles in a variety of physiological and pathophysiological processes that take place within the cardiovascular, nervous, and immune systems. Indeed, CO produced in the vessel wall by heme oxygenase enzymes possesses vasorelaxing properties and has been shown to prevent vasoconstriction and both acute and chronic hypertension through stimulation of soluble guanylate cyclase. 4 -10 Endogenous CO appears to modulate sinusoidal tone in the hepatic circulation, 11 control the proliferation of vascular smooth muscle cells 12 and suppress the rejection of transplanted hearts. 13 The biological action of heme oxygenase-derived CO is substantiated by the pharmacological effects observed when this gas is applied exogenously to in vitro and in vivo systems. At concentrations ranging from 10 to 500 ppm, CO gas has been reported to mediate potent antiinfl...

Curcumin reduces cold storage-induced damage in human cardiac myoblasts

“…HO-1 is a very effective defensive system against oxidative stress-induced cardiac cell damage (Foresti et al, 2001) as well as cardiac ischemia-reperfusion injury and organ rejection (Soares et al, 1998;Clark et al, 2003;Motterlini et al, 2005) In addition, both CO and bilirubin, the two major products of heme degradation by heme oxygenase, have been demonstrated to exert a direct and significant protective effect both in cardiac tissue (Clark et al, 2000b and during cold preservation of organs (Sandouka et al, 2006). Therefore, HO-1 induction was expected to play a major role also in the experimental protocol that we have employed in the present study.…”

“…This last aspect is of special interest for transplantation procedures as organs are usually kept at 4 o C in storage solutions before the actual transplant surgery. HO-1 and its products biliverdin, bilirubin and carbon monoxide exert beneficial effects that include protection against ischemia-reperfusion damage (Clark et al, 2000bForesti et al, 2001;Sandouka et al, 2006), mitigation of oxidative and nitrosative stress Kaur et al, 2003;Taille et al, 2005) and prolongation of graft survival of liver, heart and kidney allografts in experimental animal models of transplantation (Soares et al, 2001;Clark et al, 2003;Motterlini et al, 2005;Nakao et al, 2005). Because of its antioxidant and anti-inflammatory characteristics, the HO-1 pathway is potentially an excellent candidate to be exploited for amelioration of organ transplantation outcomes and survival Curcumin reduces cold storage-induced damage in human cardiac myoblasts Sandouka et al, 2006).…”

Carbon monoxide donors or heme oxygenase-1 (HO-1) overexpression blocks interleukin-18-mediated NF-κB–PTEN-dependent human cardiac endothelial cell death

“…Only prolonged treatment with high concentrations of CORM-1 was shown to be toxic [19]. CORM-3 (tricarbonylchloro (glycinate)ruthenium (II) ([Ru(CO) 3 Cl(glycinate)]) and inactive CORM-3 (iCORM-3) were previously described [20,21]. CORM-3 is a second generation CORM, and is an effective CO donor in vitro, ex vivo and in vitro, and does not affect cell viability for up to 50 µM [19,20].…”

Heme-arginate suppresses phospholipase C and oxidative stress in the mesenteric arterioles of mineralcorticoid-induced hypertensive rats

“…After dissolving [Ru(CO) 3 Cl 2 ] 2 in 100% dimethylsulfoxide, tricarbonylchloro(glycinato)ruthenium(II) ([Ru(CO) 3 Cl(glycinate)] or CORM-3 was prepared by adding glycine as described previously. 36 Stock solutions of CORM-3 (0.11 mol l -1 ) were prepared by dissolving the compound in distilled water. As a negative control, inactive CORM-3 (iCORM-3) was prepared by dissolving CORM-3 in phosphate-buffered saline and allowing the liberation of CO for 18 h at 37 1C in a fume hood.…”