• Medientyp: E-Artikel
  • Titel: Role of Cardiac Myocyte CXCR4 Expression in Development and Left Ventricular Remodeling After Acute Myocardial Infarction
  • Beteiligte: Agarwal, Udit; Ghalayini, Wael; Dong, Feng; Weber, Kristal; Zou, Yong-Rui; Rabbany, Sina Y.; Rafii, Shahin; Penn, Marc S.
  • Erschienen: Ovid Technologies (Wolters Kluwer Health), 2010
  • Erschienen in: Circulation Research
  • Umfang: 667-676
  • Sprache: Englisch
  • DOI: 10.1161/circresaha.110.223289
  • ISSN: 1524-4571; 0009-7330
  • Schlagwörter: Cardiology and Cardiovascular Medicine ; Physiology
  • Zusammenfassung: <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> </jats:sec> <jats:sec> <jats:title> <jats:underline>Objective:</jats:underline> </jats:title> <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. </jats:p> </jats:sec> <jats:sec> <jats:title> <jats:underline>Methods and Results:</jats:underline> </jats:title> <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> </jats:sec> <jats:sec> <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> </jats:sec>
  • Beschreibung: <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>
    </jats:sec>
    <jats:sec>
    <jats:title>
    <jats:underline>Objective:</jats:underline>
    </jats:title>
    <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.
    </jats:p>
    </jats:sec>
    <jats:sec>
    <jats:title>
    <jats:underline>Methods and Results:</jats:underline>
    </jats:title>
    <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>
    </jats:sec>
    <jats:sec>
    <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>
    </jats:sec>
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