Background-Stromal cell-derived factor-1␣ (SDF-1␣) binding to its cognate receptor, CXCR4, regulates a variety of cellular functions such as stem cell homing, trafficking, and differentiation. However, the role of the SDF-1␣-CXCR4 axis in modulating myocardial ischemia/reperfusion injury is unknown. Methods and Results-In mice subjected to ischemic preconditioning, myocardial SDF-1␣ mRNA was found to be increased 3 hours later (PϽ0.05). Myocardial SDF-1␣ and CXCR4 mRNA and protein were found to be expressed in both cardiac myocytes and fibroblasts. SDF-1␣ production increased significantly after 1 or 4 hours of hypoxia and 18 hours of reoxygenation in cultured myocytes (PϽ0.05) but did not change in fibroblast cultures. In isolated myocytes, CXCR4 activation by SDF-1␣ resulted in increased phosphorylation of both ERK 1/2 and AKT and decreased phosphorylation of JNK and p38. Cultured myocytes pretreated with SDF-1␣ were resistant to hypoxia/reoxygenation damage, exhibiting less lactate dehydrogenase release, trypan blue uptake, and apoptotic cell death (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay) (PϽ0.05). This protective effect was blocked by the CXCR4 selective antagonist AMD3100. In vivo, administration of SDF-1␣ before 30 minutes of coronary occlusion followed by 4 hours of reperfusion decreased infarct size (PϽ0.05). The decrease in infarct size with SDF-1␣ administration also was blocked by AMD3100. Conclusions-We conclude that SDF-1␣ and its receptor, CXCR4, constitute a paracrine or autocrine axis in cardiac myocytes that is activated in response to preconditioning and hypoxic stimuli, recruiting the antiapoptotic kinases ERK and AKT and promoting an antiapoptotic program that confers protection against ischemia/reperfusion damage.

Image reconstruction for magnetic resonance spectroscopic imaging (MRSI) requires specialized spatial and spectral data processing methods and benefits from the use of several sources of prior information that are not commonly available, including MRI-derived tissue segmentation, morphological analysis and spectral characteristics of the observed metabolites. In addition, incorporating information obtained from MRI data can enhance the display of low-resolution metabolite images and multiparametric and regional statistical analysis methods can improve detection of altered metabolite distributions. As a result, full MRSI processing and analysis can involve multiple processing steps and several different data types. In this paper, a processing environment is described that integrates and automates these data processing and analysis functions for imaging of proton metabolite distributions in the normal human brain. The capabilities include normalization of metabolite signal intensities and transformation into a common spatial reference frame, thereby allowing the formation of a database of MR-measured human metabolite values as a function of acquisition, spatial and subject parameters. This development is carried out under the MIDAS project (Metabolite Imaging and Data Analysis System), which provides an integrated set of MRI and MRSI processing functions. It is anticipated that further development and distribution of these capabilities will facilitate more widespread use of MRSI for diagnostic imaging, encourage the development of standardized MRSI acquisition, processing and analysis methods and enable improved mapping of metabolite distributions in the human brain.

Normal aging is associated with diminished brain perfusion measured as cerebral blood flow (CBF), but previously it is difficult to accurately measure various aspects of perfusion hemodynamics including: bolus arrival times and delays through small arterioles, expressed as arterial-arteriole transit time. To study hemodynamics in greater detail, volumetric arterial spin labeling MRI with variable postlabeling delays was used together with a distributed, dual-compartment tracer model. The main goal was to determine how CBF and other perfusion hemodynamics vary with aging. Twenty cognitive normal female and 15 male subjects (age: 23-84 years old) were studied at 4 T. Arterial spin labeling measurements were performed in the posterior cingulate cortex, precuneus, and whole brain gray matter. CBF declined with advancing age (P < 0.001). Separately from variations in bolus arrival times, arterial-arteriole transit time increased with advancing age (P < 0.01). Finally, women had overall higher CBF values (P < 0.01) and shorter arterial-arteriole transit time (P < 0.01) than men, regardless of age. The findings imply that CBF and blood transit times are compromised in aging, and these changes together with differences between genders should be taken into account when studying brain perfusion. Magn Reson Med 68:912-922,

Although transplantation of c-kit+ cardiac stem cells (CSCs) has been shown to alleviate left ventricular (LV) dysfunction induced by myocardial infarction (MI), the number of exogenous CSCs remaining in the recipient heart following transplantation and their mechanism of action remain unclear. We have previously developed a highly sensitive and accurate method to quantify the absolute number of male murine CSCs in female recipient organs after transplantation. In the present study, we used this method to monitor the number of donor CSCs in the recipient heart after intracoronary infusion. Female mice underwent a 60-min coronary occlusion followed by reperfusion; 2 days later, 100,000 c-kit+/lin- syngeneic male mouse CSCs were infused intracoronarily. Only 12.7% of the male CSCs present in the heart immediately (5 min) after infusion were still present in the heart at 24 h, and their number declined rapidly thereafter. By 35 days after infusion, only ∼1,000 male CSCs were found in the heart. Significant numbers of male CSCs were found in the lungs and kidneys, but only in the first 24 h. The number of CSCs in the lungs increased between 5 min and 24 h after infusion, indicating recirculation of CSCs initially retained in other organs. Despite the low retention and rapid disappearance of CSCs from the recipient heart, intracoronary delivery of CSCs significantly improved LV function at 35 days (Millar catheter). These results suggest that direct differentiation of CSCs alone cannot account for the beneficial effects of CSCs on LV function; therefore, paracrine effects must be the major mechanism. The demonstration that functional improvement is dissociated from survival of transplanted cells has major implications for our understanding of cell therapy. In addition, this new quantitative method of stem cell measurement will be useful in testing approaches of enhancing CSC engraftment and survival after transplantation.

. 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...