Impact of Enhanced Production of Endogenous Heme Oxygenase-1 by Pitavastatin on Survival and Functional Activities of Bone Marrow-derived Mesenchymal Stem Cells

J Cardiovasc Pharmacol. 2015 Jun;65(6):601-6. doi: 10.1097/FJC.0000000000000231.


Although mesenchymal stem cells (MSCs) have a therapeutic potential for the repair of tissue injuries, their poor viability in damaged tissue limits their effectiveness. Statins can induce an increased production of heme oxygenase-1 (HO-1), which may prevent this detrimental effect in MSCs. We investigated the protective effect of statin-induced overexpression of HO-1 by examining changes in gene expression and function in MSCs after pitavastatin treatment. The relative expression of the HO-1 and endothelial nitric oxide synthase genes in MSCs was significantly increased after treatment with pitavastatin (MSCs). Immunocytological analysis showed that MSCs also stained with phospho-Akt. After exposure to oxidative stress, MSCs showed increased resistance to induced cell death compared with control MSCs. Under serum starvation conditions, MSCs treated with 1 μM pitavastatin showed enhanced cell proliferation and a marked increase in vascular endothelial growth factor production compared with control MSCs. Interestingly, MSCs showed enhanced tube formation under both normoxia and hypoxia. These results demonstrate that pitavastatin can enhance endogenous HO-1 expression in MSCs, which may protect the cells into the environment of oxidative stress with partial activation of endothelial nitric oxide synthase and Akt phosphorylation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiogenesis Inducing Agents / pharmacology
  • Animals
  • Bone Marrow Cells / drug effects*
  • Bone Marrow Cells / enzymology
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Cells, Cultured
  • Dose-Response Relationship, Drug
  • Enzyme Activation
  • Enzyme Induction
  • Heme Oxygenase (Decyclizing) / biosynthesis*
  • Heme Oxygenase (Decyclizing) / genetics
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology*
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Male
  • Mesenchymal Stem Cells / drug effects*
  • Mesenchymal Stem Cells / enzymology
  • Neovascularization, Physiologic / drug effects
  • Nitric Oxide Synthase Type III / genetics
  • Nitric Oxide Synthase Type III / metabolism
  • Oxidative Stress
  • Phenotype
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt / metabolism
  • Quinolines / pharmacology*
  • RNA, Messenger / biosynthesis
  • Rats, Inbred Lew
  • Vascular Endothelial Growth Factor A / metabolism


  • Angiogenesis Inducing Agents
  • Hif1a protein, rat
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Quinolines
  • RNA, Messenger
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A
  • Nitric Oxide Synthase Type III
  • Nos3 protein, rat
  • Heme Oxygenase (Decyclizing)
  • Hmox1 protein, rat
  • Proto-Oncogene Proteins c-akt
  • pitavastatin