Cardioprotective effects of transforming growth factor-beta1 during early reoxygenation or reperfusion are mediated by p42/p44 MAPK.
Apoptosis contributes to myocardial cell death during ischemia and reperfusion, especially during reperfusion. Growth factor "survival" signaling attenuates apoptosis. We therefore examined the effects of transforming growth factor-beta1 (TGF-beta1) on reperfusion injury and assessed the role of p42/p44 MAPK signaling in TGF-beta1-induced protection. Rat ventricular myocytes were subjected to hypoxia and reoxygenation. TGF-beta1 (0.2 ng/ml) was applied to cells during reoxygenation and the extent of apoptosis was determined by TUNEL and annexin V binding assays. Further studies were conducted in intact rat hearts subjected to regional ischemia and reperfusion. TGF-beta1 (0.2 ng/ml) was perfused during early reperfusion. In cells, incubation with TGF-beta1 (0.2 ng/ml) during reoxygenation attenuated the extent of cell membrane damage (trypan blue uptake) and also reduced the numbers of TUNEL-and annexin V-positive cells. Reduction of apoptosis was abrogated by PD98059 (5 microM), an inhibitor of p42/p44 MAPK activation. TGF-beta1 activated p42/p44 MAPK transiently in normoxic myocytes. When intact hearts received TGF-beta1 (0.2 ng/ml) during early reperfusion, infarct size was reduced from 39.4 +/- 3.1% to 17.3 +/- 3.1% (p < 0.01). This protective action of TGF-beta1 was abrogated by PD98059. These studies are the first to show that TGF-beta attenuates cardiac myocyte apoptosis during early reperfusion and limits infarct size through p42/p44 MAPK activation.
Baxter
G F
GF
The Hatter Institute, University College, Grafton Way, London WC1E 6DB, U.K. hatter-institute@ucl.ac.uk
Mocanu
M M
MM
Brar
B K
BK
Latchman
D S
DS
Yellon
D M
DM
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects; D015687:Cell Hypoxia; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D020287:In Situ Nick-End Labeling; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000502:physiology*; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D009203:Myocardial Infarction / Q000473:pathology / Q000517:prevention & control; D015428:Myocardial Reperfusion Injury / Q000473:pathology / Q000517:prevention & control*; D009206:Myocardium / Q000201:enzymology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000494:pharmacology / Q000627:therapeutic use*; D053773:Transforming Growth Factor beta1
D004791:Enzyme Inhibitors; D005419:Flavonoids; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one