Date on Master's Thesis/Doctoral Dissertation

5-2014

Document Type

Doctoral Dissertation

Degree Name

Ph. D.

Department

Physiology and Biophysics

Degree Program

Physiology and Biophysics, PhD

Committee Chair

Rokosh, Donald

Subject

Heart failure

Abstract

Background: Interruption of cardiac stromal cell-derived factor 1 (SDF1)-CXCR4 axis by chronic AMD3100 administration increased myocardial injury after permanent coronary artery ligation, demonstrating the important role of this chemokine in cardiac regeneration. Hypothesis: Cardiomyocyte-specific conditional overexpression of SDF prevents heart failure after permanent coronary ligation and facilitates cardiac regeneration. Methods and Results: Tetracycline-controlled, a-myosine heavy chain promoter directed overexpression of cardiac SDF resulted in a significant increase of SDF expression (SDF: 8.1 ng / g protein) compared with littermate WT mice (0.02 ng / g protein) four weeks after doxycycline withdrawal. SDF overexpression increased AKT and casein kinase 1 levels in the heart. Although there was no difference in cardiac function and scar size one week after infarction, SDF overexpression improved left ventricular (LV) ejection fraction (47±5% vs. 29±4%, p < 0.05) decreased end-diastolic volume (78±10 vs. 158±30, p < 0.05) and reduced infarct size measured by trichrome staining (SDF): 13±3% vs. WT (n=15): 23±3% of LV wall, p < 0.05) four weeks after permanent ligation. Bromodeoxyuridine (BrdU) staining revealed increased regeneration indicated by a 5-fold increase in BrdU+ / a-sarcomeric actin+-cells in the border zone of the infarct (22±3% cardiomyocyte (CM) nuclei vs. 5±1% CM nuclei, p < 0.01). Increased proliferation in SDF mice was confirmed by a higher number of Ki67+ cells compared to WT mice. Cardiomyocyte cross sectional area in the border zone was significantly reduced in SDF mice (375±13 µm2 vs. 434±10 µm2, p < 0.001) while capillary density remained unchanged (2348±151 / mm2 vs. 2498±153 / mm2) compared to WT mice. Conclusion: This study demonstrates that cardiac-specific overexpression of SDF increases myocardial regeneration and improves LV function after permanent coronary ligation.

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