CXCR4 gene transfer prevents pressure overload induced heart failure.
Stem cell and gene therapies are being pursued as strategies for repairing damaged cardiac tissue following myocardial infarction in an attempt to prevent heart failure. The chemokine receptor-4 (CXCR4) and its ligand, CXCL12, play a critical role in stem cell recruitment post-acute myocardial infarction. Whereas progenitor cell migration via the CXCL12/CXCR4 axis is well characterized, little is known about the molecular mechanisms of CXCR4 mediated modulation of cardiac hypertrophy and failure. We used gene therapy to test the effects of CXCR4 gene delivery on adverse ventricular remodeling due to pressure overload. We assessed the effect of cardiac overexpression of CXCR4 during trans-aortic constriction (TAC) using a cardiotropic adeno-associated viral vector (AAV9) carrying the CXCR4 gene. Cardiac overexpression of CXCR4 in mice with pressure overload prevented ventricular remodeling, preserved capillary density and maintained function as determined by echocardiography and in vivo hemodynamics. In isolated adult rat cardiac myocytes, CXCL12 treatment prevented isoproterenol induced hypertrophy and interrupted the calcineurin/NFAT pathway. Finally, a complex involving the L-type calcium channel, β2-adrenoceptor, and CXCR4 (Cav1.2/β2AR/CXCR4) was identified in healthy cardiac myocytes and was shown to dissociate as a consequence of heart failure. CXCR4 administered to the heart via gene transfer prevents pressure overload induced heart failure. The identification of CXCR4 participation in a Cav1.2-β2AR regulatory complex provides further insight into the mechanism by which CXCR4 modulates calcium homeostasis and chronic pressure overload responses in the cardiac myocyte. Together these results suggest that AAV9.CXCR4 gene therapy is a potential therapeutic approach for congestive heart failure.
Department of Medicine, Division of Cardiovascular Research Center, Mount Sinai School of Medicine, New York 10029, USA.
Thomas J
TJ
Larocca
Dongtak
D
Jeong
Erik
E
Kohlbrenner
Ahyoung
A
Lee
Jiqiu
J
Chen
Roger J
RJ
Hajjar
Sima T
ST
Tarzami
D000818:Animals; D015153:Blotting, Western; D019703:Calcineurin / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000378:metabolism; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism; D054377:Chemokine CXCL12 / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D006333:Heart Failure / Q000235:genetics / Q000378:metabolism* / Q000628:therapy*; D006439:Hemodynamics / Q000187:drug effects; D047468:Immunoprecipitation; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D022702:Receptors, Adrenergic, beta-3 / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism*
D020746:Calcium Channels, L-Type; D054377:Chemokine CXCL12; D022702:Receptors, Adrenergic, beta-3; D019718:Receptors, CXCR4; D019703:Calcineurin; D007545:Isoproterenol