Cardioprotective effects of transforming growth factor-beta1 during early reoxygenation or reperfusion are mediated by p42/p44 MAPK.

Abstract

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.

• Authors: G F Baxter, M M Mocanu, B K Brar, D S Latchman, D M Yellon
• Journal: Journal of cardiovascular pharmacology (J Cardiovasc Pharmacol) Vol. 38 Issue 6 Pg. 930-9 (Dec 2001) ISSN: 0160-2446 [Print] United States
• PMID: 11707697 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Enzyme Inhibitors
• Flavonoids
• Tgfb1 protein, rat
• Transforming Growth Factor beta
• Transforming Growth Factor beta1
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3
• Mitogen-Activated Protein Kinases
• 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one

Topics

• Animals
• Animals, Newborn
• Apoptosis (drug effects)
• Cell Hypoxia
• Cells, Cultured
• Enzyme Inhibitors (pharmacology)
• Flavonoids (pharmacology)
• In Situ Nick-End Labeling
• Male
• Mitogen-Activated Protein Kinase 1 (antagonists & inhibitors, physiology)
• Mitogen-Activated Protein Kinase 3
• Mitogen-Activated Protein Kinases (antagonists & inhibitors, physiology)
• Myocardial Infarction (pathology, prevention & control)
• Myocardial Reperfusion Injury (pathology, prevention & control)
• Myocardium (enzymology)
• Rats
• Rats, Sprague-Dawley
• Time Factors
• Transforming Growth Factor beta (pharmacology, therapeutic use)
• Transforming Growth Factor beta1