Nerve growth factor promotes cardiac repair following myocardial infarction.
BACKGROUND
Nerve growth factor (NGF) promotes angiogenesis and cardiomyocyte survival, which are both desirable for postinfarction myocardial healing. Nonetheless, the NGF potential for cardiac repair has never been investigated.


OBJECTIVE
To define expression and localization of NGF and its high-affinity receptor TrkA (tropomyosin-related receptor A) in the human infarcted heart and to investigate the cardiac roles of both endogenous and engineered NGF using a mouse model of myocardial infarction (MI).


RESULTS
Immunostaining for NGF and TrkA was performed on heart samples from humans deceased of MI or unrelated pathologies. To study the post-MI functions of endogenous NGF, a NGF-neutralizing antibody (Ab-NGF) or nonimmune IgG (control) was given to MI mice. To investigate the NGF therapeutic potential, human NGF gene or control (empty vector) was delivered to the murine periinfarct myocardium. Results indicate that NGF is present in the infarcted human heart. Both cardiomyocytes and endothelial cells (ECs) possess TrkA, which suggests NGF cardiovascular actions in humans. In MI mice, Ab-NGF abrogated native reparative angiogenesis, increased EC and cardiomyocyte apoptosis and worsened cardiac function. Conversely, NGF gene transfer ameliorated EC and cardiomyocyte survival, promoted neovascularization and improved myocardial blood flow and cardiac function. The prosurvival/proangiogenic Akt/Foxo pathway mediated the therapeutic benefits of NGF transfer. Moreover, NGF overexpression increased stem cell factor (the c-kit receptor ligand) expression, which translated in higher myocardial abundance of c-kit(pos) progenitor cells in NGF-engineered hearts.


CONCLUSIONS
NGF elicits pleiotropic beneficial actions in the post-MI heart. NGF should be considered as a candidate for therapeutic cardiac regeneration.
Meloni
Marco
M
Experimental Cardiovascular Medicine Division, Bristol Heart Institute, Bristol, United Kingdom.
Caporali
Andrea
A
Graiani
Gallia
G
Lagrasta
Costanza
C
Katare
Rajesh
R
Van Linthout
Sophie
S
Spillmann
Frank
F
Campesi
Ilaria
I
Madeddu
Paolo
P
Quaini
Federico
F
Emanueli
Costanza
C
D000368:Aged; D000818:Animals; D017209:Apoptosis; D001344:Autopsy; D016022:Case-Control Studies; D002478:Cells, Cultured; D003326:Coronary Circulation; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D005260:Female; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism; D015316:Genetic Therapy; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D009203:Myocardial Infarction / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D018919:Neovascularization, Physiologic; D020932:Nerve Growth Factor / Q000096:biosynthesis* / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D020917:Receptor, trkA / Q000378:metabolism; D011994:Recombinant Proteins / Q000096:biosynthesis; D012038:Regeneration / Q000235:genetics; D015398:Signal Transduction; D019089:Stem Cell Factor / Q000378:metabolism; D013234:Stem Cells / Q000378:metabolism / Q000473:pathology; D013997:Time Factors; D014162:Transfection; D016277:Ventricular Function, Left
D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; C502240:NGF protein, human; D012333:RNA, Messenger; D011994:Recombinant Proteins; D019089:Stem Cell Factor; D020932:Nerve Growth Factor; D019009:Proto-Oncogene Proteins c-kit; D020917:Receptor, trkA; D051057:Proto-Oncogene Proteins c-akt