The ability of cardiac stem cells (CSCs) to promote myocardial repair under clinically relevant conditions (i.e., when delivered intravascularly after reperfusion) is unknown. Thus, rats were subjected to a 90-min coronary occlusion; at 4 h after reperfusion, CSCs were delivered to the coronary arteries via a catheter positioned into the aortic root. Echocardiographic analysis showed that injection of CSCs attenuated the increase in left ventricular (LV) end-diastolic dimensions and impairment in LV systolic performance at 5 weeks after myocardial infarction. Pathologic analysis showed that treated hearts exhibited a smaller increase in LV chamber diameter and volume and a higher wall thickness-to-chamber radius ratio and LV mass-to-chamber volume ratio. CSCs induced myocardial regeneration, decreasing infarct size by 29%. A diploid DNA content and only two chromosomes 12 were found in new cardiomyocytes, indicating that cell fusion did not contribute to tissue reconstitution. In conclusion, intravascular injection of CSCs after reperfusion limits infarct size, attenuates LV remodeling, and ameliorates LV function. This study demonstrates that CSCs are effective when delivered in a clinically relevant manner, a clear prerequisite for clinical translation, and that these beneficial effects are independent of cell fusion. The results establish CSCs as candidates for cardiac regeneration and support an approach in which the heart's own stem cells could be collected, expanded, and stored for subsequent therapeutic repair. myocardial infarction ͉ myocardial regeneration W ith the recent surge of interest in cardiac regenerative therapies for patients with acute myocardial infarction (MI) (1), the identification of clinically applicable strategies is of paramount importance. Several cell types have been used in an effort to reconstitute dead myocardium. Among them, endothelial progenitor cells and bone marrow-derived cells have been the most successful (2-6). However, preliminary long-term studies with bone marrow-derived cells indicate that the new myocytes do not acquire the adult phenotype but resemble neonatal cells, which die with time by apoptosis (P.A., unpublished data). Intense efforts continue to focus on identifying an effective cell population and an effective mode of delivery.The discovery that the adult heart contains a pool of cardiac stem cells (CSCs) that can replenish the cardiomyocyte population and generate coronary vessels (7-12) has dramatically changed the traditional view of the heart as a postmitotic organ. Because of its natural role in regeneration of cardiac cells, the endogenous CSC appears to be the ideal cell for myocardial repair. Recent studies have shown that when c-kit POS CSCs are injected directly into the myocardium adjacent to an infarct produced by a permanent coronary occlusion, they migrate to the infarct and reconstitute part of the dead tissue, reducing infarct size and ameliorating cardiac function in rats (9) and mice (12). In contrast, i.v. injection of CSCs in mice subje...

. Administration of a CO-releasing molecule at the time of reperfusion reduces infarct size in vivo. Am J Physiol Heart Circ Physiol 286: H1649-H1653, 2004. First published January 2, 2004 10.1152/ajpheart.00971.2003.-Although carbon monoxide (CO) has traditionally been viewed as a toxic gas, increasing evidence suggests that it plays an important homeostatic and cytoprotective role. Its therapeutic use, however, is limited by the side effects associated with CO inhalation. Recently, transition metal carbonyls have been shown to be a safe and effective means of transporting and releasing CO groups in vivo. The goal of the present study was to test whether a water-soluble CO-releasing molecule, tricarbonylchloro(glycinato) ruthenium (II) (CORM-3), reduces infarct size in vivo when given in a clinically relevant manner, i.e., at the time of reperfusion. Mice were subjected to a 30-min coronary artery occlusion followed by 24 h of reperfusion and were given either CORM-3 (3.54 mg/kg as a 60-min intravenous infusion starting 5 min before reperfusion) or equivalent doses of inactive CORM-3, which does not release CO. CORM-3 had no effect on arterial blood pressure or heart rate. The region at risk did not differ in control and treated mice (44.5 Ϯ 3.5% vs. 36.5 Ϯ 1.6% of the left ventricle, respectively). However, infarct size was significantly smaller in treated mice [25.8 Ϯ 4.9% of the region at risk (n ϭ 13) vs. 47.7 Ϯ 3.8% (n ϭ 14), P Ͻ 0.05]. CORM-3 did not increase carboxyhemoglobin levels in the blood. These results suggest that a novel class of drugs, CO-releasing molecules, can be useful to limit myocardial ischemia-reperfusion injury in vivo.carbon monoxide-releasing molecules; myocardial ischemia; reperfusion injury; transition metal carbonyls MAMMALIAN TISSUES continually produce carbon monoxide (CO) as a result of the breakdown of heme by heme oxygenase (HO) (13). Although CO has been traditionally regarded as toxic, recent evidence has revealed that this gas exerts pleiotropic homeostatic effects. Specifically, CO has been shown to promote vasorelaxation (12, 17) and to inhibit proliferation of smooth muscle cells (21), apoptosis (2), transplant rejection (4), inflammation (14, 15), platelet aggregation, microvascular thrombosis (3), cytokine production (9, 18), and oxidative stress (16). CO, delivered either as a gas or via CO-releasing molecules (CORMs), has also been shown to alleviate hypoxia/ reoxygenation injury in isolated cells and ischemia-reperfusion injury in isolated hearts (4) and in the liver (1). Although the mechanism(s) underlying the cytoprotective actions of CO has not been elucidated, evidence suggests that this gas exerts some of its effects via activation of the guanylate cyclase/ cGMP pathway (10, 22) and the p38 MAPK-dependent pathway (15).In view of the mounting evidence supporting a salubrious role of CO in a variety of pathophysiological conditions, much interest has focused on harnessing the actions of this molecule for therapeutic purposes. Thus far, most studies in vivo ha...

IL-6 does not modulate myocardial infarct size in naïve myocardium. However, following a PC stimulus, IL-6 is obligatorily required for the activation of the JAK-STAT pathway, the ensuing upregulation of iNOS and COX-2 (co-mediators of late PC), and the development of a cardioprotective phenotype.

No abstract

No abstract