Preconditioning promotes survival and angiomyogenic potential of mesenchymal stem cells in the infarcted heart via NF-kappaB signaling. Antioxidants & redox signaling [Antioxid Redox Signal] Journal article

We propose that pharmacological manipulation of mesenchymal stem cells (MSCs) with diazoxide enhanced their survival and regenerative potential BeginUnderlineBeginBoldvia NFkappaB regulationEndUnderlineEndBold. MSCs preconditioned (BeginSuperscriptPCEndSuperscriptMSCs) with diazoxide and later subjected to oxidant stress with 100micromol/L HBeginSubscript2End SubscriptOBeginSubscript2EndSubscript either immediately or after 24-h exhibited higher survival (BeginItalicpEndItalic<0.01 BeginItalicvsEndItalic non-preconditioned MSCs; BeginSuperscriptNon-PCEndSuperscriptMSCs) with concomitantly increased phosphorylation of PI3Kappa, Akt, GSK3beta (cytoplasmic) and NF-kappaB(p65) (nuclear). Akt kinase activity was determined as a function GSK3beta activity. Pretreatment of BeginSuperscriptPCEndSuperscriptMSCs with Wortmannin (Wt), NEMO-binding domain (NBD) or NF-kappaB(p50) siRNA abolished NF-kappaB(p65) activity. BeginUnderlineBeginBoldPreconditioning increased NF-kappaB dependent elevation of secretable growth factors associated with their paracrine effectsEndUnderlineEndBold. Inhibition of PI3K activity with Wt reduced BeginSuperscriptPCEndSuperscriptMSCs viability at both early and 24-h time-points. However, inhibition of NF-kappaB reduced viability of BeginSuperscriptPCEndSuperscriptMSCs only at 24-h time-point. Begin UnderlineBeginBoldFor in vivoEndUnderlineEndBold studies, DMEM without cells (group-1) or containing 1x10BeginSuperscript6EndSuperscript male BeginSuperscriptNon-PCEndSuperscriptMSCs (group-2), BeginSuperscriptPCEndSuperscriptMSCs (group-3), BeginSuperscriptPCEndSuperscriptMSCs pretreated with Wortmannin (group-4) or NF-kappaB decoy (group-5) were transplanted in female rat model of acute myocardial infarction. Group-3 showed highest cell survival and growth factor expression, increased angiomyogenesis and functional improvement. We conclude that activation of NF-kappaB by preconditioning promoted BeginSuperscriptPCEndSuperscriptMSCs survival and angiomyogenic potential in the infarcted heart.

Antioxidants & redox signaling [Antioxid Redox Signal]