Description:
<jats:sec>
<jats:title>
<jats:underline>Rationale:</jats:underline>
</jats:title>
<jats:p>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.</jats:p>
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<jats:title>
<jats:underline>Objective:</jats:underline>
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<jats:p>
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
<jats:sup>−/−</jats:sup>
mouse models.
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<jats:title>
<jats:underline>Methods and Results:</jats:underline>
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<jats:p>
Two strains of CM-CXCR4
<jats:sup>flox/flox</jats:sup>
mice were generated by crossing CXCR4
<jats:sup>flox/flox</jats:sup>
mice with MCM-Cre
<jats:sup>+/−</jats:sup>
mouse and MLC2v-Cre
<jats:sup>+/−</jats:sup>
mouse on the C57BL/6J background, yielding CXCR4
<jats:sup>flox/flox</jats:sup>
MCM-Cre
<jats:sup>+/−</jats:sup>
and CXCR4
<jats:sup>flox/flox</jats:sup>
MLC2v-Cre
<jats:sup>+/−</jats:sup>
mice. Studies demonstrated recombination in both models congenitally in the MLC2v-Cre
<jats:sup>+/−</jats:sup>
mice and following tamoxifen administration in the MCM-Cre
<jats:sup>+/−</jats:sup>
mice. Surprisingly the CXCR4
<jats:sup>flox/flox</jats:sup>
MLC2v-Cre
<jats:sup>+/−</jats:sup>
are viable, had normal cardiac function, and had no evidence of ventricular septal defect. CXCR4
<jats:sup>flox/flox</jats:sup>
MCM
<jats:sup>+/−</jats:sup>
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
<jats:sup>flox/flox</jats:sup>
mice versus CM-CXCR4
<jats:sup>−/−</jats:sup>
mice regardless of strategy of Cre expression. No differences in vascular density (2369±131 versus 2471±126 vessels/mm
<jats:sup>2</jats:sup>
; CXCR4
<jats:sup>flox/flox</jats:sup>
versus CM-CXCR4
<jats:sup>−/−</jats:sup>
mouse), infarct size, collagen content, or noninfarct zone cardiac myocyte size were observed 21 days after AMI.
</jats:p>
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<jats:title>
<jats:underline>Conclusions:</jats:underline>
</jats:title>
<jats:p>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.</jats:p>
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