Abstract
Granulocyte-colony stimulating factor (G-CSF) has been shown to promote mobilization of bone marrow-derived stem cells (BMCs) into the bloodstream associated with improved survival and cardiac function after myocardial infarction. Therefore, the aim of the present study was to investigate whether G-CSF is able to attenuate cardiac remodelling in a mouse model of pressure-induced LV hypertrophy focusing on mobilization and migration of BMCs. LV hypertrophy was induced by transverse aortic constriction (TAC) in C57BL/6J mice. Four weeks after TAC procedure. Mice were treated with G-CSF (100 μg/kg/day; Amgen Biologicals) for 2 weeks. The number of migrated BMCs in the heart was analysed by flow cytometry. mRNA expression and protein level of different growth factors in the myocardium were investigated by RT-PCR and ELISA. Functional analyses assessed by echocardiography and immunohistochemical analysis were performed 8 weeks after TAC procedure. G-CSF-treated animals revealed enhanced homing of VLA-4+ and c-kit+ BMCs associated with increased mRNA expression and protein level of the corresponding homing factors Vascular cell adhesion protein 1 and Stem cell factor in the hypertrophic myocardium. Functionally, G-CSF significantly preserved LV function after TAC procedure, which was associated with a significantly reduced area of fibrosis compared to control animals. Furthermore, G-CSF-treated animals revealed a significant improvement of survival after TAC procedure. In summary, G-CSF treatment preserves cardiac function and is able to diminish cardiac fibrosis after induction of LV hypertrophy associated with increased homing of VLA-4+ and c-kit+ BMCs and enhanced expression of their respective homing factors VCAM-1 and SCF.
Highlights
granulocyte-colony stimulating factor (G-CSF) treatment in mice with cardiac hypertrophy further markedly increased the number of CD45+ CD34+ VLA-4+ cells (3.4-fold; P < 0.01) and CD45+ CD34+
We wanted to investigate whether G-CSF is able to attenuate cardiac hypertrophy and fibrosis in a mouse model of pressure-induced LV hypertrophy induced by transverse aortic constriction (TAC)
TAC procedure. (ii) mRNA and Protein levels of VCAM-1- the ligand of VLA-4 and SCF- the ligand of c-kit were increased after G-CSF stimulation in the hypertrophic myocardium. (iii) G-CSF significantly reduced the area of fibrosis compared to untreated controls. (iv) Functionally, G-CSF significantly improved survival and preserved LV function after TAC procedure
Summary
LV hypertrophy accompanied by interstitial myocardial fibrosis is one of the main reasons for heart failure in patients with arterial hypertension and aortic stenosis (AS) [1]. It has been shown that cardiac fibrosis is an important morphological substrate of postoperative clinical outcome in patients with severe AS and is not completely reversible after aortic valve replacement [2]. Regeneration of ischaemic myocardial tissue has been attempted using bone marrow-derived stem cells (BMCs) and pluripotent stem cells [5, 6]. Migration of circulating mobilized BMCs from the bloodstream into the damaged tissue is suggested to play a key role for tissue regeneration [12]. The interaction of stromal cell-derived factor-1 (SDF-1/CXCL12) with its ligand chemokine receptor type 4 (CXCR4) on mobilized hematopoietic progenitor cells has been shown to play a major role in migration a 2015 The Authors
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