OBJECTIVE: Idiopathic dilated cardiomyopathy (IDCM) affects myocardial vascularization. Whether a lack of demand for increased myocardial vascularization and/or an impaired response of circulating angiogenic-supportive cells are responsible for the vascular derangements found in IDCM is unknown.
METHODS AND RESULTS: Left ventricle (LV) samples obtained at transplant from IDCM hearts were compared to control hearts from non-cardiac decedents. Peripheral colony-forming myeloid cells were extracted from age- and sex-matched IDCM patients and healthy volunteers. At the tissue level, no differences were detected in stromal cell-derived factor (SDF)-1α expression, but integrin-linked kinase (ILK) levels and activity were increased in IDCM. A marked co-localization of SDF-1α and the specific marker of cholesterol-enriched lipid rafts Flotillin (Flot)-1 was found in IDCM. SDF-1α was also highly distributed into IDCM lipid rafts. Non-adherent pro-angiogenic cells from both groups, which were found increased in patients but showed similar surface levels of CXCR-4, equally supported Matrigel-mediated cell network formation. However, SDF-1-mediated migration was reduced in IDCM-derived cells, which also exhibited decreased ILK activity and downstream ERK activation.
CONCLUSIONS: Taken together, our results point out that myocardial competency to increase vascularization is not altered in IDCM, but dysfunctional SDF-1-mediated migration by peripheral pro-angiogenic cells through ILK and downstream ERK signaling may compromise endothelial recovery in patients. We provide new insights into lipid raft function in human IDCM and envision more effective treatments.
|Number of pages||11|
|Publication status||Published - Oct 2013|
- Aged, 80 and over
- Cardiomyopathy, Dilated/pathology
- Case-Control Studies
- Cell Movement
- Chemokine CXCL12/metabolism
- Drug Combinations
- Enzyme Activation
- Extracellular Signal-Regulated MAP Kinases/metabolism
- Gene Expression Profiling
- Gene Expression Regulation
- Heart Ventricles/pathology
- Membrane Microdomains/chemistry
- Middle Aged
- Myeloid Cells/pathology
- Myocardial Ischemia/pathology
- Neovascularization, Pathologic/metabolism
- Protein-Serine-Threonine Kinases/metabolism
- Signal Transduction