Abstract
BackgroundEndothelin-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.MethodsWe 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.ResultsTAC 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.ConclusionsLack 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.
Highlights
Vascular endothelial cells are the main source of the vasoactive peptide endothelin-1 (ET-1) but cardiomyocytes, endocardial cells, and cardiofibroblasts produce ET-1 as well as its both receptors ETA and ETB [1]
Blood pressure Neither genotype nor transaortic constriction (TAC) surgery had any influence on systolic and diastolic blood pressure
The main findings of this study are that a normal expression level of ET-1 is required to maintain cardiac function after pressure overload caused by transaortic constriction and that the adverse impact of a reduced expression of ET-1 can be prevented by a pentoxifylline treatment
Summary
Vascular endothelial cells are the main source of the vasoactive peptide endothelin-1 (ET-1) but cardiomyocytes, endocardial cells, and cardiofibroblasts produce ET-1 as well as its both receptors ETA and ETB [1]. Hypertrophic, fibrotic, pro-inflammatory and inotropic effects of ET-1 contribute to the development of heart failure [4] Most of these deleterious effects are attributed to the activation of ETA receptors. Treatment with selective ETA as well as dual ETA/ETB antagonists demonstrated beneficial effects in several animal models of acute and chronic heart failure [5,6,7]. Both ETA and ETB receptors might play additive roles in the pathological cardiac remodelling [5]. The reasons for the lack of beneficial effect of endothelin antagonists in heart failure patients remain speculative. We hypothesized that blocking the pro-apoptotic TNF-a pathway using pentoxifylline could prevent the deleterious effect of the lack of ET-1 in a model for heart failure
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