Abstract
Aim. The aim of this study was to investigate whether poly(ADP-ribose) polymerase (PARP) inhibition improves endothelin-1 (ET-1)-induced endothelial dysfunction (ED).Methods. Isolated rat thoracic aorta rings were incubated with ET-1 (10 nmol/L) in the presence or absence of either polyethylene glycol–superoxide dismutase (PEG-SOD; a cell-permeable superoxide radical scavenger, 41 U/mL) plus apocynin (a NADPH oxidase inhibitor, 300 µmol/L) or PJ34 (an inhibitor of polyADP-ribose polymerase, 3 µmol/L) for 18 h. Isometric tension studies were performed in response to acetylcholine (ACh; an endothelium-dependent vasodilator), sodium nitroprusside (SNP; an endothelium-independent vasodilator), and phenylephrine (Phe). PARP-1 and PAR (an end-product of PARP activity) expressions were evaluated by both Western blot and immunohistochemistry.Results. Incubation of thoracic aorta rings with ET-1 resulted in a significant inhibition of the response to ACh, while SNP-induced relaxation was unaffected. The contractile response to Phe increased in arteries that were incubated with ET-1. PARP-1 and PAR expressions increased after ET-1 incubation. The diminished vasoreactivity as well as changes in expressions of PARP-1 and PAR in ET-1-incubated vessels were improved by both PEG-SOD plus apocynin and PJ34.Conclusion. Our studies demonstrate that ED induced by ET-1 seems to be effected via oxidative stress in the thoracic aorta endothelium with subsequent activation of the PARP pathway.
Highlights
The healthy endothelium plays an important physiological role in maintaining the cardiovascular homeostasis
We investigated whether pharmacological poly(ADP-ribose) polymerase (PARP) inhibition may represent a novel therapeutic approach in the treatment of endothelial dysfunction (ED) caused by ET-1
PARP-inhibitor treatment with PJ34 normalized the endothelial function in the ET-1-incubated thoracic aorta rings (Figure 1; p < 0.05)
Summary
The healthy endothelium plays an important physiological role in maintaining the cardiovascular homeostasis. Previous studies confirm the importance of endothelial dysfunction (ED), which is associated with the impairment of endothelium-dependent vasodilatation, in the pathophysiology of several cardiovascular diseases such as diabetes, hypertension, and heart failure [1,2,3]. ED refers to the inability of arteries and arterioles to dilate fully in response to vasodilatory stimuli such as acetylcholine or shear stress, which is associated with decreased endothelial nitric oxide (NO) bioavailability [4]. (ET-1), one of the most potent endogenous vasoconstrictor peptides, primarily generated by endothelial cells, has been reported to contribute to the pathogenesis and maintenance of ED in cardiovascular diseases [5].
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