title: Constitutive HIF-1α expression blunts the beneficial effects of cardiosphere-derived cell therapy in the heart by altering paracrine factor balance.
abstract: Hypoxia-inducible factor-1alpha (HIF-1α) expression promotes angiogenesis and can influence stem cell engraftment. We investigated the effect of stable over-expression of constitutively active HIF-1α on cardiosphere-derived cell (CDC) engraftment and left ventricular function. CDCs were transduced with a lentivirus expressing a constitutively active mutant of human HIF-1α (LVHIF-1α). Two million male rat CDCs were injected into the infarct following ligation of the mid-LAD in female syngeneic rats. Left ventricular ejection fraction (EF) and circumferential strain were measured by echocardiography at 1 and 4 weeks post-MI in the following groups: PBS group (n = 7), CELL group (n = 7), and CELL-HIF group (n = 7). HIF-1α, VEGF, endothelin-1 expression, and CDC engraftment were measured by quantitative PCR. At 30 days, EF was unchanged in the CELL-HIF group (p = NS), increased in the CELL group (p = 0.025), and decreased in the PBS group (p = 0.021), but engraftment was similar (2.4% ± 3.3% vs 1.7% ± 0.8%, p = NS). Mean circumferential strain of the infarcted region was unchanged in the CELL-HIF group, but improved in the CELL group (p = 0.02). Endothelin-1 and VEGF expression were higher in HIF-CDCs exposed to hypoxia, compared with non-transduced CDCs. HIF-1α expression in CDCs blunted the beneficial functional effects of CDC transplantation, suggesting that paracrine factor balance may play an important role in cardiac regeneration.
authors.affiliation: Johns Hopkins University, Baltimore, MD 21205, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Bonios
authors.forename: Connie Yachan
authors.initials: CY
authors.lastname: Chang
authors.forename: John
authors.initials: J
authors.lastname: Terrovitis
authors.forename: Aurelio
authors.initials: A
authors.lastname: Pinheiro
authors.forename: Andreas
authors.initials: A
authors.lastname: Barth
authors.forename: Peihong
authors.initials: P
authors.lastname: Dong
authors.forename: Miguel
authors.initials: M
authors.lastname: Santaularia
authors.forename: D Brian
authors.initials: DB
authors.lastname: Foster
authors.forename: Venu
authors.initials: V
authors.lastname: Raman
authors.forename: Theodore P
authors.initials: TP
authors.lastname: Abraham
authors.forename: Maria Roselle
authors.initials: MR
authors.lastname: Abraham
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D049109:Cell Proliferation; D004195:Disease Models, Animal; D019332:Endothelin-1 / Q000378:metabolism; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D008297:Male; D009200:Myocardial Contraction; D009203:Myocardial Infarction / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology / Q000601:surgery*; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000637:transplantation*; D018919:Neovascularization, Physiologic; D019899:Paracrine Communication; D051381:Rats; D011921:Rats, Inbred WKY; D018874:Spheroids, Cellular; D013318:Stroke Volume; D013997:Time Factors; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D016277:Ventricular Function, Left
chemical_list: D019332:Endothelin-1; C497442:HIF1A protein, human; C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D042461:Vascular Endothelial Growth Factor A; C467498:vascular endothelial growth factor A, rat