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VEGF attenuates development from cardiac hypertrophy to heart failure after aortic stenosis through mitochondrial mediated apoptosis and cardiomyocyte proliferation.

Xu XH, Xu J, Xue L, Cao HL, Liu X, Chen YJ - J Cardiothorac Surg (2011)

Bottom Line: AS for four weeks caused cardiac hypertrophy and left ventricular dysfunction.VEGF treatment increased capillary density, protected mitochondrial function, reduced CMs apoptosis, promoted CMs proliferation and eventually preserved cardiac function.Our findings indicate that VEGF could repair AS-induced transition from compensatory cardiac hypertrophy to heart failure.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Thoracic and Cardiovascular Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, P R China.

ABSTRACT

Background: Aortic stenosis (AS) affects 3 percent of persons older than 65 years and leads to greater morbidity and mortality than other cardiac valve diseases. Surgery with aortic valve replacement (AVR) for severe symptomatic AS is currently the only treatment option. Unfortunately, in patients with poor ventricular function, the mortality and long-term outcome is unsatisfied, and only a minority of these patients could bear surgery. Our previous studies demonstrated that vascular endothelial growth factor (VEGF) protects cardiac function in myocardial infarction model through classic VEGF-PI3k-Akt and unclear mitochondrial anti-apoptosis pathways; promoting cardiomyocyte (CM) proliferation as well. The present study was designed to test whether pre-operative treatment with VEGF improves AS-induced cardiac dysfunction, to be better suitable for AVR, and its potential mechanism.

Methods: Adult male mice were subjected to AS or sham operation. Two weeks later, adenoviral VEGF (Ad-VEGF), enhanced green fluorescence protein (Ad-EGFP, as a parallel control) or saline was injected into left ventricle free wall. Two weeks after delivery, all mice were measured by echocardiography and harvested for further detection.

Results: AS for four weeks caused cardiac hypertrophy and left ventricular dysfunction. VEGF treatment increased capillary density, protected mitochondrial function, reduced CMs apoptosis, promoted CMs proliferation and eventually preserved cardiac function.

Conclusions: Our findings indicate that VEGF could repair AS-induced transition from compensatory cardiac hypertrophy to heart failure.

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Related in: MedlinePlus

VEGF overexpression exerts increased capillary density, reduced CMs apoptosis, promoted CMs proliferation two weeks after viral injection. A, Representative histological micrographs of the LV myocardium stained with hematoxylin-eosin B, vWF immunostaining to identify capillary density C, Histological identification of apoptotic CMs for TUNEL D, Ki-67 staining to detect CMs proliferation E, Quantitative analysis of the cross-sectional area of CMs, and ratios of capillary, TUNEL positive nuclei and Ki-67 positive nuclei to myocyte in LV myocardium (Bars = 100 μm). *P < 0.05, TAC vs. Sham; †P < 0.05, VEGF vs. TAC.
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Figure 3: VEGF overexpression exerts increased capillary density, reduced CMs apoptosis, promoted CMs proliferation two weeks after viral injection. A, Representative histological micrographs of the LV myocardium stained with hematoxylin-eosin B, vWF immunostaining to identify capillary density C, Histological identification of apoptotic CMs for TUNEL D, Ki-67 staining to detect CMs proliferation E, Quantitative analysis of the cross-sectional area of CMs, and ratios of capillary, TUNEL positive nuclei and Ki-67 positive nuclei to myocyte in LV myocardium (Bars = 100 μm). *P < 0.05, TAC vs. Sham; †P < 0.05, VEGF vs. TAC.

Mentions: Two weeks after aorta ligature, AS mice displayed the increased LV posterior wall thickness (LVPW), interventricular septal thickness (IVSd) (P < 0.001) and similar LV fractional shortening (LVFS), LV ejection fraction (LVEF) (P = 0.92) compared with sham operated mice, indicating compensatory cardiac hypertrophy and normal systolic function (Figure 1). However at two weeks after adenoviral injection, TAC mice showed a marked LV enlargement and signs of diminished cardiac function - i.e., reduced LVEF and LVFS (P < 0.01). Treatment with Ad-VEGF prevented the reductions of LVEF and LVFS (P < 0.05), with no significant difference in LVPW, IVSd, heart weight/body weight ratio and heart weight/tibia length ratio, as compared to TAC animals (Figure 2). Histological evaluation further confirmed that the cross-sectional area of CMs increased in theses three AS groups compared to sham, although VEGF treatment had no effect on CMs hypertrophy (Figure 3A, E).


VEGF attenuates development from cardiac hypertrophy to heart failure after aortic stenosis through mitochondrial mediated apoptosis and cardiomyocyte proliferation.

Xu XH, Xu J, Xue L, Cao HL, Liu X, Chen YJ - J Cardiothorac Surg (2011)

VEGF overexpression exerts increased capillary density, reduced CMs apoptosis, promoted CMs proliferation two weeks after viral injection. A, Representative histological micrographs of the LV myocardium stained with hematoxylin-eosin B, vWF immunostaining to identify capillary density C, Histological identification of apoptotic CMs for TUNEL D, Ki-67 staining to detect CMs proliferation E, Quantitative analysis of the cross-sectional area of CMs, and ratios of capillary, TUNEL positive nuclei and Ki-67 positive nuclei to myocyte in LV myocardium (Bars = 100 μm). *P < 0.05, TAC vs. Sham; †P < 0.05, VEGF vs. TAC.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3094376&req=5

Figure 3: VEGF overexpression exerts increased capillary density, reduced CMs apoptosis, promoted CMs proliferation two weeks after viral injection. A, Representative histological micrographs of the LV myocardium stained with hematoxylin-eosin B, vWF immunostaining to identify capillary density C, Histological identification of apoptotic CMs for TUNEL D, Ki-67 staining to detect CMs proliferation E, Quantitative analysis of the cross-sectional area of CMs, and ratios of capillary, TUNEL positive nuclei and Ki-67 positive nuclei to myocyte in LV myocardium (Bars = 100 μm). *P < 0.05, TAC vs. Sham; †P < 0.05, VEGF vs. TAC.
Mentions: Two weeks after aorta ligature, AS mice displayed the increased LV posterior wall thickness (LVPW), interventricular septal thickness (IVSd) (P < 0.001) and similar LV fractional shortening (LVFS), LV ejection fraction (LVEF) (P = 0.92) compared with sham operated mice, indicating compensatory cardiac hypertrophy and normal systolic function (Figure 1). However at two weeks after adenoviral injection, TAC mice showed a marked LV enlargement and signs of diminished cardiac function - i.e., reduced LVEF and LVFS (P < 0.01). Treatment with Ad-VEGF prevented the reductions of LVEF and LVFS (P < 0.05), with no significant difference in LVPW, IVSd, heart weight/body weight ratio and heart weight/tibia length ratio, as compared to TAC animals (Figure 2). Histological evaluation further confirmed that the cross-sectional area of CMs increased in theses three AS groups compared to sham, although VEGF treatment had no effect on CMs hypertrophy (Figure 3A, E).

Bottom Line: AS for four weeks caused cardiac hypertrophy and left ventricular dysfunction.VEGF treatment increased capillary density, protected mitochondrial function, reduced CMs apoptosis, promoted CMs proliferation and eventually preserved cardiac function.Our findings indicate that VEGF could repair AS-induced transition from compensatory cardiac hypertrophy to heart failure.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Thoracic and Cardiovascular Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, P R China.

ABSTRACT

Background: Aortic stenosis (AS) affects 3 percent of persons older than 65 years and leads to greater morbidity and mortality than other cardiac valve diseases. Surgery with aortic valve replacement (AVR) for severe symptomatic AS is currently the only treatment option. Unfortunately, in patients with poor ventricular function, the mortality and long-term outcome is unsatisfied, and only a minority of these patients could bear surgery. Our previous studies demonstrated that vascular endothelial growth factor (VEGF) protects cardiac function in myocardial infarction model through classic VEGF-PI3k-Akt and unclear mitochondrial anti-apoptosis pathways; promoting cardiomyocyte (CM) proliferation as well. The present study was designed to test whether pre-operative treatment with VEGF improves AS-induced cardiac dysfunction, to be better suitable for AVR, and its potential mechanism.

Methods: Adult male mice were subjected to AS or sham operation. Two weeks later, adenoviral VEGF (Ad-VEGF), enhanced green fluorescence protein (Ad-EGFP, as a parallel control) or saline was injected into left ventricle free wall. Two weeks after delivery, all mice were measured by echocardiography and harvested for further detection.

Results: AS for four weeks caused cardiac hypertrophy and left ventricular dysfunction. VEGF treatment increased capillary density, protected mitochondrial function, reduced CMs apoptosis, promoted CMs proliferation and eventually preserved cardiac function.

Conclusions: Our findings indicate that VEGF could repair AS-induced transition from compensatory cardiac hypertrophy to heart failure.

Show MeSH
Related in: MedlinePlus