Rationale: Angiogenesis is a crucial step towards tissue repair and regeneration after ischemia. The role of circulating exosomes in angiogenic signal transduction has not been well elucidated. Thus, this study aims to investigate the effects of coronary serum exosomes from patients with myocardial ischemia on angiogenesis and to elucidate the underlying mechanisms.Methods and Results: The patients were enrolled according to the inclusion and exclusion criteria. Coronary blood was obtained from the angiography catheter. Serum exosomes were purified and characterized by their specific morphology and surface markers. In vitro analysis showed that compared to exosomes from healthy controls (con-Exo), exosomes from patients with myocardial ischemia (isc-Exo) enhanced endothelial cell proliferation, migration and tube formation. In a mouse hind-limb ischemia model, blood perfusion and histological staining demonstrated that isc-Exo significantly promoted blood flow recovery and enhanced neovascularization compared to con-Exo. Further, we revealed that cardiomyocytes, but not cardiac fibroblasts or endothelial cells, were initiated to release exosomes under ischemic stress; cardiomyocytes might be the source of bioactive exosomes in coronary serum. In addition, microarray analysis indicated that miR-939-5p was significantly down-regulated in isc-Exo. By knockdown and overexpression analyses, we found that miR-939-5p regulated angiogenesis by targeting iNOS. miR-939-5p inhibited both iNOS's expression and its activity, attenuated endothelial NO production, and eventually impaired angiogenesis.Conclusions: Exosomes derived from patients with myocardial ischemia promote angiogenesis via the miR-939-iNOS-NO pathway. Our study highlights that coronary serum exosomes serve as an important angiogenic messenger in patients suffering from myocardial ischemia.

IntroductionType II cryoglobulinemia, a lymphoproliferative disorder characterized by cold-precipitable immune complexes composed of polyclonal immunoglobulin (Ig)-G and monoclonal IgM rheumatoid factor (mRF), predominantly occurs secondary to hepatitis C virus (HCV) infection (HCV-type II cryogloblulinemia). The concentration of HCV in type II cryoglobulins and the presence of a highly restricted mRF bearing the WA cross-idiotype in approximately 80% of patients lead to the hypothesis that proliferation of the WA mRF-producing cells was driven by HCV. 1,2 Moreover, recent data demonstrated that contrary to the premise that type II cryoglobulinemia is a low-grade malignancy, 3 the oligoclonal B-cell expansion frequently present in the bone marrow of these patients showed no evidence of malignancy. 4 In this study, we present a patient with HCV-type II cryoglobulinemia, a leukemiclike monoclonal B-cell proliferation bearing marginal zone B-cell (MZBC) phenotypic markers without definitive evidence of malignancy, Bcl-2 overexpression, and partial trisomy 3. The course of the patient's disease is informative because this is the first report of partial trisomy 3 and Bcl-2 overexpression in HCV-type II cryoglobulemia, and there was a synchronous decrease in B-cell proliferation and viremia with interferon-␣ therapy. Study design Index caseA 57-year-old white male with HCV-type II cryoglobulinemia in clinical remission for 10 years relapsed in March 1998 and presented with palpable purpura, cryoglobulinemia (4% cryocrit), marked leukocytosis (white blood cell [WBC] count, 35.7 ϫ 10 9 /L), and splenomegaly. Other notable laboratory findings were the following: positive HCV serology and HCV RNA; anemia (hemoglobin 116 g/L); normal platelet count (151 ϫ 10 9 /L); low C4 component of complement (7 mg/dL; normal range, 17-45 mg/dL); high lactate dehydrogenase (LDH) (843 IU/mL; normal range, 325-685 IU/mL); high IgM (3.05 g/L; normal range, 0.5-2 g/L) with a monoclonal IgM ; low IgG (3.64 g/L; normal range, 7.5-14 g/L); but normal IgA (1.55 g/L; normal range, 0.75-3.1 g/L). There was no clinical evidence of renal or liver disease. A chest and abdominal computed tomography (CT) scan showed a normal liver, a 20.6 ϫ 11.2 cm spleen, and no adenopathy. Bone marrow examination showed multifocal clusters of small atypical lymphocytes suspicious for lymphoproliferative disorder. Lymphocyte phenotypes for peripheral blood and bone marrow were identical: IgM ϩ , ϩ , IgD Ϫ , CD19 ϩ , CD20 ϩ , CD22 ϩ , CD5 Ϫ , CD10 Ϫ , CD23 Ϫ ; villous lymphocytes were not present. Treatment with interferon (IFN) was initiated. Longitudinal studies from April 8, 1998, to September 24, 1999, are shown in Figure 1. Subsequently, cryoglobulinemia remained in remission with no clinical evidence of malignancy. CT scans performed in February and May 2001 showed no lymphadenopathy and spleen measurements of 14 ϫ 6 cm and 13 ϫ 6 cm, respectively. The patient expired in June 2001 from complications of atherosclerotic peripheral vascular disease. An autopsy was...

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