Constitutive HIF-1α expression blunts the beneficial effects of cardiosphere-derived cell therapy in the heart by altering paracrine factor balance

Michael Bonios, Connie Yachan Chang, John Terrovitis, Aurelio Pinheiro, Andreas Barth, Peihong Dong, Miguel Santaularia, D. Brian Foster, Venu Raman, Theodore P. Abraham, Maria Roselle Abraham

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)363-372
Number of pages10
JournalJournal of Cardiovascular Translational Research
Volume4
Issue number3
DOIs
StatePublished - Jun 1 2011

Keywords

  • Animal models of human disease
  • Cardiac regeneration
  • Cardiosphere-derived cells
  • Constitutively active HIF-1α
  • Echocardiography
  • Myocardial infarction
  • Paracrine factor balance

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Pharmaceutical Science
  • Cardiology and Cardiovascular Medicine
  • Genetics(clinical)

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