Fenofibrate Reverses Dysfunction of EPCs Caused by Chronic Heart Failure
- 3 Downloads
The enhanced activity of endothelial progenitor cells (EPCs) by AMP-activated protein kinase (AMPK) agonists might explain the reversal of chronic heart failure (CHF)–mediated endothelial dysfunction. We studied baseline circulating EPC numbers in patients with heart failure and clarified the effect of fenofibrate on both circulating angiogenic cell (CAC) and late EPC activity. The numbers of circulating EPCs in CHF patients were quantified by flow cytometry. Blood-derived mononuclear cells were cultured, and CAC and late EPC functions, including fibronectin adhesion, tube formation, and migration, were evaluated. We focused on the effect of fenofibrate, an AMPK agonist, on EPC function and Akt/eNOS cascade activation in vitro. The number of circulating EPCs (CD34+/KDR+) was significantly lower in CHF patients (ischemic cardiomyopathy (ICMP): 0.07%, dilated cardiomyopathy (DCMP): 0.068%; p < 0.05) than in healthy subjects (0.102% of the gating region). In CACs, fibronectin adhesion function was reversed by fenofibrate treatment (p < 0.05). Similar results were also found for tube formation and migration in late EPCs, which were significantly improved by fenofibrate in an AMPK-dependent manner (p < 0.05), suggesting that fenofibrate reversed CACs and late EPC dysfunction in CHF patients. The present findings reveal the potential application of the AMPK agonist fenofibrate to reverse endothelial dysfunction in CHF patients.
KeywordsChronic heart failure Endothelial progenitor cell eNOS AMPK Fenofibrate
Endothelial progenitor cells
Circulating angiogenesis cells
Chronic heart failure
Peripheral blood mononuclear cells
Vascular endothelial growth factor receptor 2
Peroxisome proliferator–activated receptors
Left ventricular ejection fraction
AMP-dependent protein kinase
- Compound C
This study was supported, in part, by research grants from the Ministry of Science and Technology of Taiwan (MOST 104-2314-B-075-047), the Novel Bioengineering and Technological Approaches to Solve Two Major Health Problems in Taiwan sponsored by the Taiwan Ministry of Science and Technology Academic Excellence Program (MOST 108-2633-B-009-001), the Ministry of Health and Welfare (MOHW106-TDU-B-211-113001), and Taipei Veterans General Hospital (V105C-0207, V106C-045). The funders had no role in the study design, data collection, data analysis, decision to publish, or preparation of the manuscript.
Compliance with Ethical Standards
Conflict of Interest
The authors declare that they have no conflict of interest.
Human Subjects/Informed Consent Statement
The Human Investigation Committee of the Cheng-Hsin Rehabilitation Medical Center approved the study protocol (CHGH-IRB: (136) 97-17-2). All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000(5). Informed consent was obtained from all patients included in the study.
- 23.Lee, W. H., & Kim, S. G. (2010). AMPK-dependent metabolic regulation by PPAR agonists. PPAR Research, 2010(2010).Google Scholar
- 28.Shaffer, R. G., Greene, S., Arshi, A., Supple, G., Bantly, A., et al. (2006). Flow cytometric measurement of circulating endothelial cells: The effect of age and peripheral arterial disease on baseline levels of mature and progenitor populations. Cytometry. Part B, Clinical Cytometry, 70, 56–62.PubMedCrossRefGoogle Scholar
- 34.Yoon, C. H., Hur, J., Park, K. W., Kim, J. H., Lee, C. S., et al. (2005). Synergistic neovascularization by mixed transplantation of early endothelial progenitor cells and late outgrowth endothelial cells: The role of angiogenic cytokines and matrix metalloproteinases. Circulation, 112, 1618–1627.PubMedCrossRefGoogle Scholar
- 35.Urao, N., Okigaki, M., Yamada, H., Aadachi, Y., Matsuno, K., et al. (2006). Erythropoietin-mobilized endothelial progenitors enhance reendothelialization via Akt-endothelial nitric oxide synthase activation and prevent neointimal hyperplasia. Circulation Research, 98, 1405–1413.PubMedCrossRefGoogle Scholar
- 36.Kissel, C. K., Lehmann, R., Assmus, B., Aicher, A., Honold, J., et al. (2007). Selective functional exhaustion of hematopoietic progenitor cells in the bone marrow of patients with postinfarction heart failure. Journal of the American College of Cardiology, 49, 2341–2349.PubMedCrossRefGoogle Scholar
- 37.Assmus, B., Fischer-Rasokat, U., Honold, J., Seeger, F. H., Fichtlscherer, S., et al. (2007). Transcoronary transplantation of functionally competent BMCs is associated with a decrease in natriuretic peptide serum levels and improved survival of patients with chronic postinfarction heart failure: Results of the TOPCARE-CHD registry. Circulation Research, 100, 1234–1241.PubMedCrossRefGoogle Scholar
- 45.Procopio, C., Andreozzi, F., Laratta, E., Cassese, A., Beguinot, F., et al. (2009). Leptin-stimulated endothelial nitric-oxide synthase via an adenosine 5′-monophosphate-activated protein kinase/Akt signaling pathway is attenuated by interaction with C-reactive protein. Endocrinology, 150, 3584–3593.PubMedCrossRefGoogle Scholar