TY - JOUR
T1 - Constitutive HIF-1α expression blunts the beneficial effects of cardiosphere-derived cell therapy in the heart by altering paracrine factor balance
AU - Bonios, Michael
AU - Chang, Connie Yachan
AU - Terrovitis, John
AU - Pinheiro, Aurelio
AU - Barth, Andreas
AU - Dong, Peihong
AU - Santaularia, Miguel
AU - Brian Foster, D.
AU - Raman, Venu
AU - Abraham, Theodore P.
AU - Abraham, Maria Roselle
N1 - Funding Information:
Sources of Funding This study was supported by the WW Smith Foundation (West Conshohocken, PA; MRA), AHA (Dallas, TX; MRA), Maryland TEDCO (Columbia, MD; MRA), NIH RO1 HL092985 (Bethesda, MD; MRA/FB), and GE healthcare (Waukesha, WI).
PY - 2011/6
Y1 - 2011/6
N2 - Hypoxia-inducible factor-1alpha (HIF-1α) expression promotes angiogenesis and can influence stem cell engraftment. We investigated the effect of stable overexpression of constitutively active HIF-1α on cardiospherederived 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.
AB - Hypoxia-inducible factor-1alpha (HIF-1α) expression promotes angiogenesis and can influence stem cell engraftment. We investigated the effect of stable overexpression of constitutively active HIF-1α on cardiospherederived 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.
KW - Animal models of human disease
KW - Cardiac regeneration
KW - Cardiosphere-derived cells
KW - Constitutively active HIF-1α
KW - Echocardiography
KW - Myocardial infarction
KW - Paracrine factor balance
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U2 - 10.1007/s12265-011-9265-3
DO - 10.1007/s12265-011-9265-3
M3 - Article
C2 - 21538185
AN - SCOPUS:79960563927
SN - 1937-5387
VL - 4
SP - 363
EP - 372
JO - Journal of cardiovascular translational research
JF - Journal of cardiovascular translational research
IS - 3
ER -