期刊
BASIC RESEARCH IN CARDIOLOGY
卷 108, 期 6, 页码 -出版社
SPRINGER HEIDELBERG
DOI: 10.1007/s00395-013-0388-3
关键词
Postmyocarditic virus-induced cardiomyopathy; Bone marrow-derived progenitor cells; Vascular cell adhesion molecule-1; Granulocyte colony-stimulating factor
资金
- Fritz-Bender-Stiftung
- FoFoLe program of the LMU Munich
- DFG
- Dr. Helmut Legerlotz-Stiftung
- Else Kroner-Fresenius-Stiftung
- DFG [SFB-TR19]
- BMBF [01EZ0817]
Endogenous circulation of bone marrow-derived cells (BMCs) was observed in patients with dilated cardiomyopathy (DCM) who showed cardiac upregulation of Vascular Cell Adhesion Protein-1 (VCAM-1). However, the underlying pathophysiology is currently unknown. Thus, we aimed to analyze circulation, migration and G-CSF-based mobilization of BMCs in a murine model of virus-induced DCM. Mice with coxsackievirus B3 (CVB3) induced DCM and healthy controls were analyzed regarding their myocardial homing factors by PCR. To determine cardiac VCAM-1 expression ELISA and immunohistochemistry were applied. Flow cytometry was performed to analyze BMCs. Cardiac diameters and function were evaluated by echocardiography before and 4 weeks after G-CSF treatment. In murine CVB3-induced DCM an increase of BMCs in peripheral blood and a decrease of BMCs in bone marrow was observed. We found an enhanced migration of Very Late Antigen-4 (VLA-4(+)) BMCs to the diseased heart overexpressing VCAM-1 and higher numbers of CD45(-)CD34(-)Sca-1(+) and CD45(-)CD34(-)c-kit(+) cells. Mobilization of BMCs by G-CSF boosted migration along the VCAM-1/VLA-4 axis and reduced apoptosis of cardiomyocytes. Significant improvement of cardiac function was detected by echocardiography in G-CSF-treated mice. Blocking VCAM-1 by a neutralizing antibody reduced the G-CSF-dependent effects on stem cell migration and cardiac function. This is the first study showing that in virus-induced DCM VCAM-1/VLA-4 interaction is crucial for recruitment of circulating BMCs leading to beneficial anti-apoptotic effects resulting in improved cardiac function after G-CSF-induced mobilization.
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