Fibroblast growth factor-2-induced cardioprotection against myocardial infarction occurs via the interplay between nitric oxide, protein kinase signaling, and ATP-sensitive potassium channels.
Fibroblast growth factor-2 (FGF2) protects the heart from ischemia-reperfusion (I-R) injury via a vast network of protein kinases. In the heart, downstream effectors of these FGF2-triggered signals have not yet been identified. It is hypothesized that nitric oxide (NO) signaling and ATP-sensitive potassium (K(ATP)) channel activity are key effectors of protein kinases activated by FGF2-mediated cardioprotection. Hearts with a cardiac-specific overexpression of FGF2 (FGF2 Tg) were subjected to I-R injury in the absence or the presence of selective inhibitors of NO synthase (NOS) isoforms or sarcolemmal (sarcK(ATP)) and mitochondrial (mitoK(ATP)) K(ATP) channels. Multiple NOS isoforms are necessary for FGF2-mediated cardioprotection, and nitrite levels are significantly reduced in FGF2 Tg hearts upon inhibition of protein kinase C or mitogen-activated protein kinases. Likewise, sarcK(ATP) and mitoK(ATP) channels are important for cardioprotection elicited by endogenous FGF2. These findings suggest that FGF2-induced cardioprotection occurs via protein kinase-NOS pathways as well as K(ATP) channel activity.
Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
Janet R
JR
Manning
Gregory
G
Carpenter
Darius R
DR
Porter
Stacey L
SL
House
Daniel A
DA
Pietras
Thomas
T
Doetschman
Jo el J
Jel J
Schultz
D000818:Animals; D004789:Enzyme Activation; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism*; D006801:Humans; D054086:KATP Channels / Q000378:metabolism*; D051379:Mice; D009203:Myocardial Infarction / Q000378:metabolism / Q000517:prevention & control*; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D015221:Potassium Channels / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism*; D015427:Reperfusion Injury / Q000378:metabolism; D012508:Sarcolemma / Q000378:metabolism; D015398:Signal Transduction; D015854:Up-Regulation
D054086:KATP Channels; D015221:Potassium Channels; C117780:mitochondrial K(ATP) channel; D016222:Fibroblast Growth Factor 2; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D011494:Protein Kinases