The extent of myocardial damage contributes to the elevation of serum VEGF levels in AMI. VEGF produced by PBMCs may play an important role in the improvement of left ventricular function by promoting angiogenesis and reendothelialization after AMI.

Previously, we reported that a novel subpopulation of young mesenchymal stem cells (YMSCs) existed in old bone marrow, which possessed high antiaging properties as well as excellent efficacy for cardiac repair. MicroRNAs (miRNAs) have emerged as key regulators in posttranscriptional gene expression programs, and however, it is unknown whether miRNAs directly control stem cell senescence. Here we present the first evidence that miR-195 overexpressed in old MSCs (OMSCs) induces stem cell senescence deteriorating their regenerative ability by directly deactivating telomerase reverse transcriptase (Tert), and abrogation of miR-195 can reverse stem cell aging. MiRNAs profiling analysis in YMSCs and OMSCs by microarray showed that miR-140, miR-146a/b, and miR-195 were significantly upregulated in OMSCs, which led us to hypothesize that these are age-induced miRNAs involved in stem cell senescence. Of these miRNAs, we found SIGNIFICANCE STATEMENTIn this study, we investigated the role of miRNAs involved in stem cell aging and their impact on cardiac repair. Here we report our novel findings that regenerative ability of aged stem cells is deteriorated by increased expression of miR-195 which targets telomerase reverse transcriptase (Tert) gene, and abrogation of miR-195 in aged stem cells markedly induces Tert reactivation, resulting in significant telomere re-lengthening. Additionally, we show that transplantation of aged stem cells lacking miR-195 significantly reduced infarction size and concomitant improvement of cardiac function. These findings demonstrate that silencing miR-195 reverses the senescence clock in aged stem cells by telomerase reactivation. The strategy of modification of miRs in stem cells holds great promise for stem cell based repair of aging myocardium.

Objective-Endothelial progenitor cells (EPCs) play an important role in the self-healing of a vascular injury by participating in the reendothelialization that limits vascular remodeling. We evaluated whether prostaglandin I 2 plays a role in the regulation of the function of EPCs to limit vascular remodeling. Ϫ cKit ϩ Flk-1 ϩ cells) were isolated from the bone marrow (BM) of wild-type (WT) mice or mice lacking the prostaglandin I 2 receptor IP (IP Ϫ/Ϫ mice). Reverse transcription-polymerase chain reaction analysis showed that EPCs among BM cells specifically express IP. The cellular properties of EPCs, adhesion, migration, and proliferation on fibronectin were significantly attenuated in IP-deficient EPCs compared with WT EPCs. In contrast, IP agonists facilitated these functions in WT EPCs, but not in IP-deficient EPCs. The specific deletion of IP in BM cells, which was performed by transplanting BM cells of IP Ϫ/Ϫ mice to WT mice, accelerated wire injury-mediated neointimal hyperplasia in the femoral artery. Notably, transfused WT EPCs, but not IP-deficient EPCs, were recruited to the injured vessels, participated in reendothelialization, and efficiently rescued the accelerated vascular remodeling. Key Words: vascular remodeling Ⅲ prostaglandin I 2 Ⅲ endothelial progenitor cells Ⅲ fibronectin Ⅲ adhesion V ascular remodeling characterized by neointimal hyperplasia frequently accompanies angioplasty and atherosclerosis. 1 The development of vascular remodeling is limited by a process of reendothelialization, 2 which is accomplished by covering the neointimal surface with a functional endothelial monolayer. Recently, endothelial progenitor cells (EPCs) have been established as the cells participating in reendothelialization. 3,4 EPCs, which originate in bone marrow (BM), are mobilized into peripheral circulation in response to vascular injury. 5,6 After mobilization, they are recruited to the injured vessels, differentiate into mature endothelial cells, and contribute to reendothelialization to a variable extent depending on the nature of the vascular injury. 7-9 Accordingly, the infusion of exogenous EPCs 8,9 or EPC-mobilizing factors, 7,10 which increases circulatory EPCs, facilitated reendothelialization of the injured vessels and thereby suppressed neointimal formation. Methods and Results-EPCs (Lin Conclusion-These See accompanying article on page 457Prostaglandin (PG) I 2 (prostacyclin), a potent antiatherogenic lipid mediator, is the major prostanoid in the cardiovascular system and is produced mainly by vascular endothelial cells. PGI 2 exerts a variety of actions via binding to the specific receptor IP and, thus, induces vascular relaxation, inhibits proliferation of vascular smooth muscle cells, and potently inhibits platelet activation. 11 Accordingly, mice lacking the IP (IP Ϫ/Ϫ mice) have shown the phenotypes characterized by enhanced vascular remodeling with augmented neointimal hyperplasia after a vascular injury 12 and by facilitated atherosclerosis when having a concomitant loss of apoprote...

Background-The beneficial effects of thermal therapy have been reported in several cardiovascular diseases. However, it is unknown whether the thermal treatment has some beneficial roles against the development of atherosclerosis. Methods and Results-The inflammatory arterial lesion was introduced by placement of a polyethylene cuff on femoral arteries of male Sprague-Dawley rats for 4 weeks. Thermal-treated group underwent daily bathing in 41°C hot water for 15 minutes. Neointimal thickening along with immunohistochemical expression of heat-shock proteins (HSPs), monocyte chemoattractant protein-1 (MCP-1), and NADPH oxidase were compared with those of a thermally untreated (Control) group. Morphometric analysis demonstrated a significant suppression of neointimal thickening in thermal-treated group compared with the Control group (intimal/medial area ratios, 0.01Ϯ0.01 versus 0.31Ϯ0.04, PϽ0.01). Expression of MCP-1 and infiltration of ED-positive cells were enhanced in the adventitial layer of Control. More importantly, expression of HSP72 in media was enhanced by thermal treatment. Expression of p22-phox, the major membrane subunit of NADPH oxidase, and MCP-1 was augmented in cuff-injured adventitia of the Control but not the thermal-treated groups. Conclusions-Thermal treatment significantly attenuated infiltration of inflammatory cells in adventitia and suppressed neointimal thickening in cuff-injured arteries with the enhancement of HSP72 expression and suppression of oxidative stress.