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Objective:
Objective of the study was to explore the effects on heart of knocking out VEGFR2 gene in mice subjected to myocardial infarction (MI) and also its effect on miRNA profile
Design:
Preclinical Animal Study; Mice were divided into 4 groups(n=6-10/group): Wild type sham(WTSHAM); WTMI; Knockout Sham(KOSHAM) and KOMI
Setting:
Molecular Cardiology Laboratory, University Research Facility
Patients:
N/A
Interventions:
Wild type(WT) and knockout(KO) animal were randomised and underwent MI/SHAM surgery. MI was induced by LAD ligation
Main Outcome Measures:
miScript miRNA PCR array was performed 24 hours after MI. Immunohistochemical analysis and functional assessment of cardiac function with echocardiography, was done 30 days after MI
Results:
Post-infarction, systolic function showed significant reduction of ejection fraction and fractional shortening in KOMI group compared to WTMI [EF (28.21±1.02(n=6) vs. 37±0.71%(n=6), p<0.05) and FS (13.24±0.52(n=6) vs. 17.94±0.39%(n=6), p<0.05)]. We also observed decreased capillary density [2048±98.84(n=6) vs. 2443±69.84(n=9), p<0.05] in KOMI compared to WTMI. Myocardial fibrosis measured by picrosirrus red staining were more evident in the KOMI compared to WTMI (17.51±1.09(n=6) vs. 8.37±0.79%(n=6), p<0.05). Disruption of Flk-1 (KOMI) induced measurable changes in miRNA profile compared to the corresponding WT group. Out of 41 differentially regulated miRNAs found in KOMI, miR-21, miR-150, miR-92a, miR-106B play key roles in the regulation of angiogenesis and miR-9, miR-15a, miR-15b, miR-182, miR-503 are known to regulate cell death and survivability. These, miRs are the important targets of VEGFR2/Flk-1 through which VEGF induces pro-angiogenic and cardioprotective activities.
Conclusions:
Our study, shows the disruption of the Flk-1 receptor in a murine MI model causes impaired angiogenesis, increased fibrosis and reduced cardiac function presumably via the modulation of these identified miRNAs and their respective target genes