Background-Stromal cell-derived factor-1 (SDF-1) is a chemoattractant of stem/progenitor cells, and several studies haveshown that SDF-1 may improve ventricular function after infarction. SDF-1 is cleaved by proteases including matrix metalloproteinase-2 (MMP-2) and CD26/dipeptidylpeptidase-4 (DPP-4), which are activated in injured tissues. Methods and Results-We investigated the biodistribution and functional roles of SDF-1 in experimental ischemia/ reperfusion injury in rats. Radiolabeled SDF-1 given by intracoronary injection was selectively concentrated in ischemic myocardium. The enhanced uptake of SDF-1 in ischemic myocardium was not mediated by its receptor, CXCR4. Mass spectrometry and Western analyses showed that SDF-1 was cleaved by DPP-4 in plasma and myocardium, whereas a bioengineered MMP-2/DPP-4 -resistant form of SDF-1, SSDF-1(S4V), was highly stable. A single dose of SSDF-1(S4V) exhibited greater potency for cardioprotection than wild-type SDF-1. SSDF-1(S4V) improved cardiac function in rats even after a 3-hour ischemic period. Conclusions-These results show that a single dose of protease-resistant SSDF-1(S4V) after myocardial infarction leads to dramatic improvement in angiogenesis and ventricular function even 3 hours after the onset of ischemia, revealing a simple, clinically feasible approach to prevention of heart failure. (Circ Heart Fail. 2011;4:509-518.)Key Words: myocardium Ⅲ ischemia Ⅲ cardioprotection Ⅲ angiogenesis Ⅲ reperfusion Ⅲ heart failure P atients with myocardial infarction (MI) benefit from early myocardial reperfusion, which is the most effective strategy to improve clinical outcome. 1 Despite the success of reperfusion, mortality and morbidity after MI remain substantial, with 5% to 6% of patients having a subsequent cardiovascular event in the next 30 days. 1 Therefore, novel cardioprotective strategies are required to improve clinical outcomes in patients with ischemic heart disease. [2][3][4] Clinical Perspective on p 518Stromal cell-derived factor-1 (SDF-1, also known as CXCL12) is a chemokine that binds to specific G-proteincoupled 7-transmembrane receptors presented on the plasma membranes of target cells. 5 SDF-1 binds to at least 1 chemokine receptor, CXCR4, and SDF-1 and CXCR4 deficient mice display similar lethal phenotypes. 6,7 SDF-1 secreted by bone marrow during embryogenesis is critical for the colonization of marrow by fetal liver-derived hematopoietic stem/progenitor cells. 8 Furthermore, during adult life, SDF-1 has a pivotal role in the retention and homing of hematopoietic stem/progenitor cells into the bone marrow microenvironment through the interaction with CXCR4. 9 Recent studies from multiple laboratories have demonstrated that SDF-1 treatment after MI recruits hematopoietic stem cells from the circulation or bone marrow and exert beneficial effects on ventricular function, probably through inhibition of cardiomyocyte apoptosis and the promotion of angiogenesis. 10 -14 SDF-1 is susceptible to cleavage and inactivation by several proteases, including m...

Animal models exhibiting high homology with humans at the genetic and pathophysiological levels will facilitate identification and validation of gene targets underlying asthma. In the present study, a nonhuman primate model of allergic asthma was developed by sensitizing cynomolgus monkeys to dust mite antigen. Sensitization elevated allergen-specific serum IgE and IgG levels, and peripheral blood mononuclear cells isolated from sensitized animals released IL-4, IL-5, and IL-10, but not IFN-gamma. Aerosolized allergen decreased dynamic compliance and induced airway inflammation and hyperresponsiveness to aerosolized histamine. Albuterol and dexamethasone inhibited the airway constriction and allergen-induced inflammation, respectively. Airway wall remodeling that included goblet cell hyperplasia, basement membrane thickening, and smooth muscle hypertrophy was particularly evident in neonatally sensitized animals. In contrast to animals sensitized as adults, neonatally sensitized animals exhibited increased sensitivity to adenosine and larger allergen-induced changes in airway resistance and dynamic compliance. These results demonstrate that sensitization of cynomolgus monkeys with dust mite induces asthmalike symptoms, some of which may be dependent on age at the time of sensitization.