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Published on: June 3, 2019
Sirtuin 1 ablation in endothelial cells is associated with impaired angiogenesis and diastolic dysfunction
Julien Maizel1, Sandhya Xavier2, Jun Chen2
1Medical Intensive Care Unit, Department of Nephrology and INSERM U-1088, University of Picardie, Amiens, France; Department of Medicine, Renal Research Institute, New York Medical College, Valhalla, New York julien.maizel@u-picardie.fr.
Insights
Endothelial Sirtuin 1 deficiency impairs angiogenesis, leading to diastolic dysfunction and worsened heart failure in mice, especially under stress. This highlights Sirtuin 1
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Aging Research
Background:
- Aging is associated with declining Sirtuin 1 (SIRT1) expression and increased risk of heart failure.
- Discordant myocardial growth and angiogenesis contribute to left ventricular (LV) hypertrophy and heart failure with aging.
- The specific role of endothelial SIRT1 in age-related cardiomyopathy and angiogenesis remains unclear.
Purpose of the Study:
- To investigate the role of endothelial Sirtuin 1 in the development of cardiomyopathy and angiogenesis during aging.
- To determine the impact of endothelial Sirtuin 1 deletion on cardiac function and angiogenic capacity under normal and stressed conditions.
Main Methods:
- Comparison of cardiac function, capillary density, and molecular markers in endothelial Sirtuin 1-deleted (Sirt1(endo-/-)) mice and controls at different ages (10-15, 30-40, 61-70 weeks).
- Induction of transverse aortic constriction (TAC) to model LV pressure overload in Sirt1(endo-/-) and control mice.
- Assessment of in vitro endothelial cell function and ex vivo aortic explant capillary sprouting.
Main Results:
- Sirt1(endo-/-) mice developed diastolic dysfunction and reduced capillary density by 30-40 weeks, independent of LV fibrosis or hypoxia-inducible factor 1α (HIF1α) expression.
- TAC in Sirt1(endo-/-) mice exacerbated diastolic dysfunction and fibrosis, with persistent reduced capillary density despite elevated HIF1α.
- Endothelial Sirtuin 1 inhibition reduced VEGF receptor expression, and Sirt1(endo-/-) mice showed impaired ex vivo angiogenic response to VEGF.
Conclusions:
- A defect in angiogenesis precedes diastolic dysfunction in aging hearts.
- Endothelial Sirtuin 1 is dispensable under unstressed conditions but crucial for angiogenic adaptation.
- Impaired angiogenesis due to endothelial Sirtuin 1 deficiency aggravates diastolic dysfunction under LV overload.
Abstract:
Discordant myocardial growth and angiogenesis can explain left ventricular (LV) hypertrophy progressing toward heart failure with aging. Sirtuin 1 expression declines with age; therefore we explored the role played by angiogenesis and Sirtuin 1 in the development of cardiomyopathy. We compared the cardiac function of 10- to 15-wk-old (wo), 30-40 wo, and 61-70 wo endothelial Sirtuin 1-deleted (Sirt1(endo-/-)) mice and their corresponding knockout controls (Sirt1(Flox/Flox)). After 30-40 wk, Sirt1(endo-/-) animals exhibited diastolic dysfunction (DD), decreased mRNA expression of Serca2a in the LV, and decreased capillary density compared with control animals despite a similar VEGFa mRNA expression. However, LV fibrosis and hypoxia-inducible factor (HIF)1α expression were not different. The creation of a transverse aortic constriction (TAC) provoked more severe DD and LV fibrosis in Sirt1(endo-/-) compared with control TAC animals. Although the VEGFa mRNA expression was not different and the protein expression of HIF1α was higher in the Sirt1(endo-/-) TAC animals, capillary density remained reduced. In cultured endothelial cells administration of Sirtuin 1 inhibitor decreased mRNA expression of VEGF receptors FLT 1 and FLK 1. Ex vivo capillary sprouting from aortic explants showed impaired angiogenic response to VEGF in the Sirt1(endo-/-) mice. In conclusion, the data demonstrate 1) a defect in angiogenesis preceding development of DD; 2) dispensability of endothelial Sirtuin 1 under unstressed conditions and during normal aging; and 3) impaired angiogenic adaptation and aggravated DD in Sirt1(endo-/-) mice challenged with LV overload.
