In this study the time course of homing and the body distribution of systemically delivered bone marrow mesenchymal stem cells (BM-MSCs) after myocardial infarction (MI) were evaluated. BM-MSCs were isolated from Wistar rats, expanded in vitro, and their phenotypical characterization was performed by flow cytometer. Rats were randomly divided into three groups: control, sham MI, and MI. BM-MSCs (5 × 10 6 ) were labeled with 99m Tc-HMPAO and injected through the tail vein 7 days after MI. Gamma camera imaging was performed at 5, 15, 30, and 60 min after cell inoculation. Due to the 99m Tc short half-life, cell migration and location were also evaluated in heart sections using DAPI-labeled cells 7 days after transplantation. Phenotypical characterization showed that BM-MSCs were CD90 + , CD73 + , CD54+ , and CD45 − . Five minutes after 99m Tc-HMPAO-labeled cell injection, they were detected in various tissues. The cells migrated mainly to the lungs (approximately 70%) and, in small amounts, to the heart, kidneys, spleen, and bladder. The number of cells in the heart and lungs decreased after 60 min. MI markedly increased the amount of cells in the heart, but not in the lungs, during the period of observation (4.55 ± 0.32 vs. 6.34 ± 0.67% of uptake in infarcted hearts). No significant differences were observed between control and sham groups. Additionally, 7 days after DAPI-labeled cells injection, they were still detected in the heart but only in infarcted areas. These results suggest that the migration of systemically delivered BM-MSCs to the heart is time dependent and MI specifically increases BM-MSCs homing to injured hearts. However, the systemic delivery is limited by cell entrapment in the lungs.Key words: Myocardial infarction; Mesenchymal stem cells; Homing; Body distribution INTRODUCTIONstem cells (BM-MSCs) that can differentiate into different cellular types (5,14,27). Many reports have shown that cellular therapy using Mesenchymal stem cells (MSCs) have been isolated from multiple adult tissue sources, such as cord blood, BM-MSCs is able to improve cardiac function after myocardial ischemia in different species, including huplacenta, adipose and dermal tissues, synovial fluid, deciduous teeth, and amniotic fluid (19). This broad distrimans (2,30). However, the mechanisms by which BMMSCs induce their beneficial effects in the heart are still bution of sources combined with their ability to differentiate into multiple mesenchymal phenotypes, such as controversial. Thus, it has been proposed that BM-MSCs can differentiate into both vascular endothelial cells and bone, cartilage, tendon, and adipose tissue, has led them to be referred as potential therapeutic candidates for sevcardiomyocytes, activate local factors, fuse with resident cells, or even a combination of these mechanisms that eral diseases and degenerative processes, including myocardial infarction (MI) (18,37). In addition to these ultimately lead to a restoration of the cardiac structure and function (6,7,32 based therapy for myocardial repai...

The nonpeptide AVE-0991, which has been reported as a selective ligand for the angiotensin-(1-7) [ANG-(1-7)] receptor Mas, has actions similar to those attributed to the cardioprotective product of the renin-angiotensin system, ANG-(1-7). In this study, we evaluated the cardiac effects of AVE-0991 in normal and infarcted male Wistar rats. Myocardial infarction was induced by left coronary artery ligation. At the end of the treatment, the Langendorff technique was used to analyze cardiac function. Left ventricle serial sections were dyed with Gomori trichrome stain to quantify the infarcted area. In normal hearts, AVE-0991 produced a significant decrease in perfusion pressure and an increase in systolic tension, rate of tension rise and fall (+/-dT/dt), and heart rate. These effects were completely blocked by the perfusion of the hearts with a solution containing the selective ANG-(1-7) antagonist A-779. N(G)-nitro-l-arginine methyl ester treatment abolished the AVE-0991-induced vasodilation in isolated hearts. AVE-0991 significantly attenuated the decrease in systolic tension (sham operated, 13.00 +/- 1.02 g; infarction, 7.18 +/- 0.66 g; AVE treated, 9.23 +/- 1.05 g, n = 5), +dT/dt, -dT/dt, and heart rate induced by myocardial infarction. Infarction-induced vasoconstriction was completely prevented by AVE-0991 treatment. Furthermore, AVE-0991 significantly decreased the infarcted area (6.98 +/- 1.01 vs. 3.94 +/- 1.04 mm(2) in AVE-treated rats). These data indicate that the compound AVE-0991 produces beneficial effects in isolated perfused rat hearts involving the ANG-(1-7) receptor Mas and the release of nitric oxide. In addition, our results indicate that AVE-0991 attenuates postischemic heart failure.

In this study we evaluated the cardiac effects of a pharmaceutical formulation developed by including angiotensin (Ang)-(1-7) in hydroxypropyl β-cyclodextrin (HPβCD), in normal, infarcted, and isoproterenol-treated rats. Myocardial infarction was produced by left coronary artery occlusion. Isoproterenol (2 mg/kg, IP) was administered daily for 7 days. Oral administration of HPβCD/Ang-(1-7) started immediately before infarction or associated with the first dose of isoproterenol. After 7 days of treatment, the rats were euthanized, and the Langendorff technique was used to analyze cardiac function. In addition, heart function was chronically (15, 30, 50 days) analyzed by echocardiography. Cardiac sections were stained with hematoxylin/eosin and Masson trichrome to evaluate cardiac hypertrophy and damage, respectively. Pharmacokinetic studies showed that oral HPβCD/Ang-(1-7) administration significantly increased Ang-(1-7) on plasma whereas with the free peptide it was without effect. Oral administration of HPβCD/Ang-(1-7) (30 μg/kg) significantly reduced the deleterious effects induced by myocardial infarction on systolic and diastolic tension, ±dT/dt, perfusion pressure, and heart rate. Strikingly, a 50% reduction of the infarcted area was observed in HPβCD/Ang-(1-7)-treated rats. Furthermore, HPβCD/Ang-(1-7) attenuated the heart function impairment and cardiac remodeling induced by isoproterenol. In infarcted rats chronically treated with HPβCD/Ang-(1-7), the reduction of ejection fraction and fractional shorting and the increase in systolic and diastolic left ventricular volumes observed in infarcted rats were attenuated. Altogether, these findings further confirm the cardioprotective effects of Ang-(1-7). More importantly, our data indicate that the HPβCD/Ang-(1-7) is a feasible formulation for oral administration of Ang-(1-7), which can be used as a cardioprotective drug.