TY - JOUR
T1 - Intracoronary mesenchymal stem cells promote postischemic myocardial functional recovery, decrease inflammation, and reduce apoptosis via a signal transducer and activator of transcription 3 mechanism
AU - Poynter, Jeffrey A.
AU - Herrmann, Jeremy L.
AU - Manukyan, Mariuxi C.
AU - Wang, Yue
AU - Abarbanell, Aaron M.
AU - Weil, Brent R.
AU - Brewster, Benjamin D.
AU - Meldrum, Daniel R.
N1 - Funding Information:
This work was supported in part by NIH grants R01GM070628 (DRM), R01HL085595 (DRM), 1F32HL092718 (AMA), 1F32HL092719 (JLH), and 1F32HL093987 (BRW).
PY - 2011/8
Y1 - 2011/8
N2 - Background: Signal transducer and activator of transcription 3 (STAT3) regulates myocardial apoptosis, cellular proliferation, and the immune response after ischemia/reperfusion (I/R). STAT3 is also necessary for the production of vascular endothelial growth factor (VEGF) by mesenchymal stem cells (MSCs), which are known to reduce myocardial injury after I/R. However, it remains unknown whether STAT3 is an important mediator of MSC-based cardioprotection. We hypothesized that knockout of stem cell STAT3 would reduce MSC-derived myocardial functional recovery and increase myocardial inflammatory and apoptotic signaling. Study Design: With a Langendorff apparatus, male rat hearts were subjected to 15 minutes of equilibration and 25 minutes of ischemia, followed by 40 minutes of reperfusion. Immediately before ischemia, hearts received intracoronary infusions of vehicle, wild-type MSCs (WT MSCs) or STAT3 knockout MSCs (STAT3KO MSCs). Heart function was measured continuously. Myocardial homogenates were analyzed for production of interleukin (IL)-1, IL-6, and tumor necrosis factor-α (TNF-α). Additionally, MSC production of hepatocyte growth factor (HGF) and insulin-like growth factor-1 (IGF-1) were measured in vitro. Results: Hearts treated with WT MSCs exhibited the greatest functional recovery, and those treated with STAT3KO MSCs had equivalent recovery to vehicle. The highest proinflammatory cytokine levels were seen in vehicle-treated hearts, and the lowest in the WT MSC group. STAT3KO MSCs produced less IGF-1, but more HGF than WT MSCs. Finally, hearts treated with STAT3KO MSCs or vehicle had significantly higher caspase-3 levels than those treated with WT MSCs. Conclusions: Intracoronary infusions of MSCs improve postischemic left ventricular function and reduce proapoptotic and proinflammatory signaling via a STAT3-dependent mechanism.
AB - Background: Signal transducer and activator of transcription 3 (STAT3) regulates myocardial apoptosis, cellular proliferation, and the immune response after ischemia/reperfusion (I/R). STAT3 is also necessary for the production of vascular endothelial growth factor (VEGF) by mesenchymal stem cells (MSCs), which are known to reduce myocardial injury after I/R. However, it remains unknown whether STAT3 is an important mediator of MSC-based cardioprotection. We hypothesized that knockout of stem cell STAT3 would reduce MSC-derived myocardial functional recovery and increase myocardial inflammatory and apoptotic signaling. Study Design: With a Langendorff apparatus, male rat hearts were subjected to 15 minutes of equilibration and 25 minutes of ischemia, followed by 40 minutes of reperfusion. Immediately before ischemia, hearts received intracoronary infusions of vehicle, wild-type MSCs (WT MSCs) or STAT3 knockout MSCs (STAT3KO MSCs). Heart function was measured continuously. Myocardial homogenates were analyzed for production of interleukin (IL)-1, IL-6, and tumor necrosis factor-α (TNF-α). Additionally, MSC production of hepatocyte growth factor (HGF) and insulin-like growth factor-1 (IGF-1) were measured in vitro. Results: Hearts treated with WT MSCs exhibited the greatest functional recovery, and those treated with STAT3KO MSCs had equivalent recovery to vehicle. The highest proinflammatory cytokine levels were seen in vehicle-treated hearts, and the lowest in the WT MSC group. STAT3KO MSCs produced less IGF-1, but more HGF than WT MSCs. Finally, hearts treated with STAT3KO MSCs or vehicle had significantly higher caspase-3 levels than those treated with WT MSCs. Conclusions: Intracoronary infusions of MSCs improve postischemic left ventricular function and reduce proapoptotic and proinflammatory signaling via a STAT3-dependent mechanism.
KW - HGF
KW - I/R
KW - IGF
KW - IMDM
KW - Iscove's modified Dulbecco's medium
KW - KO
KW - MSC
KW - STAT 3
KW - TNF
KW - VEGF
KW - WT
KW - hepatocyte growth factor
KW - insulin-like growth factor
KW - ischemia/reperfusion
KW - knockout
KW - mesenchymal stem cell
KW - signal transducer and activator of transcription 3
KW - tumor necrosis factor
KW - vascular endothelial growth factor
KW - wild-type
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U2 - 10.1016/j.jamcollsurg.2011.04.005
DO - 10.1016/j.jamcollsurg.2011.04.005
M3 - Article
C2 - 21546276
AN - SCOPUS:79960844090
SN - 1072-7515
VL - 213
SP - 253
EP - 260
JO - Journal of the American College of Surgeons
JF - Journal of the American College of Surgeons
IS - 2
ER -