| Rationale:Neovascularization, anti-apoptosis, anti-inflammation and fibrosis therapies were identified as effective treatments to prevent cardiac remodeling after myocardial infarction (MI). Several lines of evidence indicate that syndecan 4 (synd4) is involved in tissue damage-repairing procedure, including neovascularization, inflammation and fibrosis. Recently, syndecan 1, another member of syndecan family, was discovered as a protective molecular in MI. Here we explored therapeutic potential of synd4 in cardiac infarction using an Adenoviral vector-mediated gene delivery.Methods and results:Echocardiography, hemodynamic assessment and brain natriuretic peptide (BNP) revealed that exogenous synd4 expression significantly improved heart function. Results from histological studies showed synd4 expression in myocardium resulted in attenuating cardiac remodeling. We further observed significant neovascularization in the treated group by immunohistochemistry of CD31, vwF and a-SMA. Using human umbilical vein endothelial cells (HUVECs) we discovered that synd4 expression promoted synd4 self-clusterization and activation of downstream PKC-a and Akt, leading to improved ability in cell migration, proliferation and tube formation. In myocardium and incubated myocardiocytes, synd4 expression could significantly reduce cell apoptosis via PKC-a and Akt pathway by DNA ladder and Tunel assay. In the end, there were reduced leukocytes (CD45+) and myofibroblast (a-SMA+) in synd4 treated myocardium. Inflammation molecular MCP-1. TNF-βand TG2 were also down-regulated in tissue by realtime PCR. Therefore increased synd4 expression could induce angiogenesis, protect myocardiocyte from apoptosis, and suppress tissue inflammation and fibrosis, resulted in improved heart function and cardiac remodeling post MI.Conclusions:Our study argues that synd4-mediated signaling pathway is potentially a novel therapeutic target for myocardial infarction. |
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