FGF1/p38 MAP kinase inhibitor therapy induces cardiomyocyte mitosis, reduces scarring, and rescues function after myocardial infarction.
Mammalian cardiomyocytes have limited proliferation potential, and acutely injured mammalian hearts do not regenerate adequately. Instead, injured myocardium develops fibrosis and scarring. Here we show that FGF1/p38 MAP kinase inhibitor treatment after acute myocardial injury in 8- to 10-week-old rats increases cardiomyocyte mitosis. At 3 months after injury, 4 weeks of FGF1/p38 MAP kinase inhibitor therapy results in reduced scarring and wall thinning, with markedly improved cardiac function. In contrast, p38 MAP kinase inhibition alone fails to rescue heart function despite increased cardiomyocyte mitosis. FGF1 improves angiogenesis, possibly contributing to the survival of newly generated cardiomyocytes. Our data indicate that FGF1 and p38 MAP kinase, proteins involved in cardiomyocyte proliferation and angiogenesis during development, may be delivered therapeutically to enhance cardiac regeneration.
Engel
Felix B
FB
Department of Pediatrics, Harvard Medical School, Children's Hospital, 320 Longwood Avenue, Boston, MA 02115, USA. engel@enders.tch.harvard.edu
Hsieh
Patrick C H
PC
Lee
Richard T
RT
Keating
Mark T
MT
D000818:Animals; D002921:Cicatrix / Q000378:metabolism / Q000473:pathology; D004791:Enzyme Inhibitors / Q000378:metabolism* / Q000627:therapeutic use; D016220:Fibroblast Growth Factor 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007093:Imidazoles / Q000378:metabolism* / Q000627:therapeutic use; D008297:Male; D008938:Mitosis / Q000502:physiology; D009203:Myocardial Infarction / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000166:cytology / Q000473:pathology / Q000502:physiology*; D011725:Pyridines / Q000378:metabolism* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D012038:Regeneration / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
D004791:Enzyme Inhibitors; D007093:Imidazoles; D011725:Pyridines; D016220:Fibroblast Growth Factor 1; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580