Role of cardiac myocyte CXCR4 expression in development and left ventricular remodeling after acute myocardial infarction.
BACKGROUND
Stromal cell-derived factor (SDF)-1/CXCR4 axis has an instrumental role during cardiac development and has been shown to be a potential therapeutic target for optimizing ventricular remodeling after acute myocardial infarction (AMI) and in ischemic cardiomyopathy. Although a therapeutic target, the specific role of cardiac myocyte CXCR4 (CM-CXCR4) expression following cardiogenesis and survival of cardiac myocyte and left ventricular remodeling after AMI is unknown.


OBJECTIVE
We hypothesized that cardiac myocyte derived CXCR4 is critical for cardiac development, but it may have no role in adulthood secondary to the short transient expression of SDF-1 and the delayed expression of CM-CXCR4 following AMI. To address this issue, we developed congenital and conditional CM-CXCR4(-/-) mouse models.


RESULTS
Two strains of CM-CXCR4(flox/flox) mice were generated by crossing CXCR4(flox/flox) mice with MCM-Cre(+/-) mouse and MLC2v-Cre(+/-) mouse on the C57BL/6J background, yielding CXCR4(flox/flox) MCM-Cre(+/-) and CXCR4(flox/flox)MLC2v-Cre(+/-) mice. Studies demonstrated recombination in both models congenitally in the MLC2v-Cre(+/-) mice and following tamoxifen administration in the MCM-Cre(+/-) mice. Surprisingly the CXCR4(flox/flox)MLC2v-Cre(+/-) are viable, had normal cardiac function, and had no evidence of ventricular septal defect. CXCR4(flox/flox)MCM(+/-) treated with tamoxifen 2 weeks before AMI demonstrated 90% decrease in cardiac CXCR4 expression 48 hours after AMI. Twenty-one days post AMI, echocardiography revealed no statistically significant difference in the wall thickness, left ventricular dimensions or ejection fraction (40.9+/-7.5 versus 34.4+/-2.6%) in CXCR4(flox/flox) mice versus CM-CXCR4(-/-) mice regardless of strategy of Cre expression. No differences in vascular density (2369+/-131 versus 2471+/-126 vessels/mm(2); CXCR4(flox/flox) versus CM-CXCR4(-/-) mouse), infarct size, collagen content, or noninfarct zone cardiac myocyte size were observed 21 days after AMI.


CONCLUSIONS
We conclude that cardiac myocyte-derived CXCR4 is not essential for cardiac development and, potentially because of the mismatch in timings of peaks of SDF-1 and CXCR4, has no major role in ventricular remodeling after AMI.
Agarwal
Udit
U
Departments of Cardiovascular Medicine and Stem Cell Biology, Cleveland Clinic, 9500 Euclid Ave., Cleveland, OH 44195, USA.
Ghalayini
Wael
W
Dong
Feng
F
Weber
Kristal
K
Zou
Yong-Rui
YR
Rabbany
Sina Y
SY
Rafii
Shahin
S
Penn
Marc S
MS
D000818:Animals; D024722:Cardiac Myosins / Q000235:genetics; D002465:Cell Movement; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D019426:Integrases / Q000235:genetics; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D018995:Myosin Heavy Chains / Q000235:genetics; D018994:Myosin Light Chains / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection; D016277:Ventricular Function, Left; D020257:Ventricular Remodeling
C514936:CXCR4 protein, mouse; D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D018994:Myosin Light Chains; D012333:RNA, Messenger; D019718:Receptors, CXCR4; C107184:myosin light chain 2; C045073:Cre recombinase; D019426:Integrases; D024722:Cardiac Myosins; D018995:Myosin Heavy Chains