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Updated: May 3, 2026
Surgically Induced Cardiac Volume Overload by Aortic Regurgitation in Mouse
Published on: August 30, 2022
Vascular endothelium derived endothelin-1 is required for normal heart function after chronic pressure overload in
Susi Heiden1, Nicolas Vignon-Zellweger1, Shigeru Masuda2
1Department of Clinical Pharmacy, Kobe Pharmaceutical University, Kobe, Japan.
Insights
Endothelial endothelin-1 (ET-1) deficiency worsens heart failure under pressure overload. Pentoxifylline shows therapeutic potential by improving cardiac function independently of TNF-α in this model.
Area of Science:
- Cardiovascular Research
- Molecular Cardiology
- Pharmacology
Background:
- Endothelin-1 (ET-1) plays a role in heart failure pathophysiology.
- The limited success of ET-1 antagonists in heart failure patients may stem from ET-1's anti-apoptotic effects on cardiomyocytes.
- This study investigates if blocking TNF-α with pentoxifylline can counteract the negative impact of ET-1 deficiency in heart failure.
Purpose of the Study:
- To investigate the role of endothelial ET-1 in pressure overload-induced heart failure.
- To evaluate the therapeutic effect of pentoxifylline in a mouse model of heart failure with endothelial ET-1 deficiency.
- To explore the mechanism of pentoxifylline's action, particularly its relation to the TNF-α pathway.
Main Methods:
- Transaortic constriction (TAC) was performed on wild-type (WT) and endothelial cell-specific ET-1 deficient (VEETKO) mice.
- Mice were treated with pentoxifylline for twelve weeks post-TAC.
- Cardiac function, hypertrophy, apoptosis, and gene expression (TNF-α, caspase-3/8, ANP, BNP, bcl2, bax) were assessed.
Main Results:
- TAC induced cardiac hypertrophy and reduced fractional shortening in VEETKO mice, but not WT mice.
- Pentoxifylline prevented cardiac hypertrophy and functional decline in VEETKO mice.
- Pentoxifylline treatment reduced BNP and bcl2 expression, suggesting a TNF-α-independent beneficial effect.
Conclusions:
- Endothelial ET-1 is crucial for maintaining cardiac function under pressure overload.
- Pentoxifylline demonstrates therapeutic potential in a subset of heart failure patients with ET-1 deficiency.
- The beneficial effects of pentoxifylline appear to be mediated through TNF-α-independent pathways.
Background:
Endothelin-1 participates in the pathophysiology of heart failure. The reasons for the lack of beneficial effect of endothelin antagonists in heart failure patients remain however speculative. The anti-apoptotic properties of ET-1 on cardiomyocytes could be a reasonable explanation. We therefore hypothesized that blocking the pro-apoptotic TNF-α pathway using pentoxifylline could prevent the deleterious effect of the lack of ET-1 in a model for heart failure.
Methods:
We performed transaortic constriction (TAC) in vascular endothelial cells specific ET-1 deficient (VEETKO) and wild type (WT) mice (n = 5-9) and treated them with pentoxifylline for twelve weeks.
Results:
TAC induced a cardiac hypertrophy in VEETKO and WT mice but a reduction of fractional shortening could be detected by echocardiography in VEETKO mice only. Cardiomyocyte diameter was significantly increased by TAC in VEETKO mice only. Pentoxifylline treatment prevented cardiac hypertrophy and reduction of fractional shortening in VEETKO mice but decreased fractional shortening in WT mice. Collagen deposition and number of apoptotic cells remained stable between the groups as did TNF-α, caspase-3 and caspase-8 messenger RNA expression levels. TAC surgery enhanced ANP, BNP and bcl2 expression. Pentoxifylline treatment reduced expression levels of BNP, bcl2 and bax.
Conclusions:
Lack of endothelial ET-1 worsened the impact of TAC-induced pressure overload on cardiac function, indicating the crucial role of ET-1 for normal cardiac function under stress. Moreover, we put in light a TNF-α-independent beneficial effect of pentoxifylline in the VEETKO mice suggesting a therapeutic potential for pentoxifylline in a subpopulation of heart failure patients at higher risk.
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