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. 2008 Feb 19;28(11):3790–3803. doi: 10.1128/MCB.01580-07

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Copyright © 2008, American Society for Microbiology

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FIG. 1. — Targeted deletion of VHL in cardiac myocytes leads to cardiomegaly, progressive heart failure, tumor formation, and cardiac death. (A) Cardiac myocyte-specific deletion of VHL (VHL^−/−) results in development of severe cardiomegaly relative to what is seen for hearts from age- and sex-matched littermates (VHL^+/+). (B) Short-axis two-dimensional (2-D) echocardiography (orientation of ultrasound slice depicted at left) demonstrates severe left ventricular dilation in VHL^−/− hearts. For VHL^+/+ and VHL^−/− hearts, the image on the right is an enlargement of the short-axis image. The yellow lines depict relative intraventricular diameters during diastole. (C) Long-axis two-dimensional echocardiography (orientation depicted at left) demonstrating chamber dilation and the presence of a tumor in the left atrium. LV, left ventricle; RV, right ventricle; LA, left atrium; the yellow arrow depicts a tumor. (D) Echocardiographic analysis of cardiac function reveals significantly reduced fractional shortening during contraction of VHL^−/− hearts and significant increases in both end-diastolic and end-systolic diameters of the left ventricle. Whereas these differences were significant at 5 months postbirth, these differences were not significant at 4 months, thus demonstrating the temporal progression of dysfunction and dilation. n ≥ 10 mice per genotype. FS, fractional shortening; LVEDD, left ventricular end-diastolic diameter; LVESD, left ventricular end-systolic diameter; 4m and 5m, 4 and 5 months postbirth; ctrl, control littermates; KO, VHL^−/−. (E) Hemodynamic assessment reveals reduced rates of pressure increase and pressure decrease during left ventricular contraction in VHL^−/− hearts (+dP/dt and −dP/dt, respectively) and reduced peak developed pressures in VHL^−/− hearts at baseline and during progressive infusion rates of dobutamine. Heart rates were similar in VHL^−/− and VHL^+/+ (control littermate) hearts at all but the highest dose of dobutamine. (F) Heart weights and heart weight/body weight ratios were higher for the cmVHL^−/− mice (n ≥ 12 per genotype). (G) Cardiac deletion of VHL results in early and progressive mortality, beginning after 3 months postbirth. Concomitant deletion of VHL and HIF-1α in heart muscle prevents this increased mortality. dKO, double knockout. Curve generated with ≥20 mice per genotype.

FIG. 1. — Targeted deletion of VHL in cardiac myocytes leads to cardiomegaly, progressive heart failure, tumor formation, and cardiac death. (A) Cardiac myocyte-specific deletion of VHL (VHL^−/−) results in development of severe cardiomegaly relative to what is seen for hearts from age- and sex-matched littermates (VHL^+/+). (B) Short-axis two-dimensional (2-D) echocardiography (orientation of ultrasound slice depicted at left) demonstrates severe left ventricular dilation in VHL^−/− hearts. For VHL^+/+ and VHL^−/− hearts, the image on the right is an enlargement of the short-axis image. The yellow lines depict relative intraventricular diameters during diastole. (C) Long-axis two-dimensional echocardiography (orientation depicted at left) demonstrating chamber dilation and the presence of a tumor in the left atrium. LV, left ventricle; RV, right ventricle; LA, left atrium; the yellow arrow depicts a tumor. (D) Echocardiographic analysis of cardiac function reveals significantly reduced fractional shortening during contraction of VHL^−/− hearts and significant increases in both end-diastolic and end-systolic diameters of the left ventricle. Whereas these differences were significant at 5 months postbirth, these differences were not significant at 4 months, thus demonstrating the temporal progression of dysfunction and dilation. n ≥ 10 mice per genotype. FS, fractional shortening; LVEDD, left ventricular end-diastolic diameter; LVESD, left ventricular end-systolic diameter; 4m and 5m, 4 and 5 months postbirth; ctrl, control littermates; KO, VHL^−/−. (E) Hemodynamic assessment reveals reduced rates of pressure increase and pressure decrease during left ventricular contraction in VHL^−/− hearts (+dP/dt and −dP/dt, respectively) and reduced peak developed pressures in VHL^−/− hearts at baseline and during progressive infusion rates of dobutamine. Heart rates were similar in VHL^−/− and VHL^+/+ (control littermate) hearts at all but the highest dose of dobutamine. (F) Heart weights and heart weight/body weight ratios were higher for the cmVHL^−/− mice (n ≥ 12 per genotype). (G) Cardiac deletion of VHL results in early and progressive mortality, beginning after 3 months postbirth. Concomitant deletion of VHL and HIF-1α in heart muscle prevents this increased mortality. dKO, double knockout. Curve generated with ≥20 mice per genotype.