Role of cardiac myocyte CXCR4 expression in development and left ventricular remodeling after acute myocardial infarction
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Permanent Ligation of the Left Anterior Descending Coronary Artery in Mice: A Model of Post-myocardial Infarction Remodelling and Heart Failure
Published on: December 2, 2014
Udit Agarwal1, Wael Ghalayini, Feng Dong
1Departments of Cardiovascular Medicine and Stem Cell Biology, Cleveland Clinic, 9500 Euclid Ave., Cleveland, OH 44195, USA.
Rationale:
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.
Methods And 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.
Insights
Cardiac myocyte CXCR4 is not essential for heart development and plays no significant role in ventricular remodeling after myocardial infarction. This finding impacts potential therapeutic strategies targeting the SDF-1/CXCR4 axis in cardiac conditions.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Regenerative Medicine
Background:
- The Stromal cell-derived factor (SDF)-1/CXCR4 axis is crucial for cardiac development.
- CXCR4 in cardiac myocytes (CM-CXCR4) is a potential therapeutic target for myocardial infarction (AMI) and ischemic cardiomyopathy.
- The specific role of CM-CXCR4 post-cardiogenesis and after AMI remains unclear.
Purpose of the Study:
- To investigate the role of cardiac myocyte-derived CXCR4 in cardiac development and post-AMI ventricular remodeling.
- To test the hypothesis that CM-CXCR4 is critical for development but not essential in adulthood due to temporal expression mismatches.
Main Methods:
- Generated congenital and conditional cardiac myocyte-specific CXCR4 knockout (CM-CXCR4-/-) mouse models.
- Utilized Cre-lox recombination strategies (MLC2v-Cre and MCM-Cre) for CXCR4 deletion.
- Assessed cardiac function, ventricular remodeling, vascular density, infarct size, and myocyte size post-AMI.
Main Results:
- Congenital CM-CXCR4 knockout mice were viable with normal cardiac function and no septal defects.
- Conditional knockout mice exhibited a 90% decrease in cardiac CXCR4 post-tamoxifen administration before AMI.
- No significant differences in cardiac function, dimensions, wall thickness, vascularization, infarct size, or myocyte size were observed between knockout and control mice post-AMI.
Conclusions:
- Cardiac myocyte-derived CXCR4 is dispensable for normal cardiac development.
- CM-CXCR4 does not play a major role in ventricular remodeling following acute myocardial infarction.
- Temporal asynchrony between SDF-1 and CXCR4 expression likely contributes to the lack of significant impact post-AMI.
