Role Of endothelin-B Receptors Research Articles

Sovateltide (IRL-1620) activates neuronal differentiation and prevents mitochondrial dysfunction in adult mammalian brains following stroke

The development of effective drugs for stroke is urgently required as it is the 2nd largest killer in the world and its incidence is likely to increase in the future. We have demonstrated cerebral endothelin B receptors (ETBR) as a potential target to treat acute cerebral ischemic stroke. However, the mechanism of ETBR mediated neural regeneration and repair remains elusive. In this study, a permanent middle cerebral artery occluded (MCAO) rat model was used. Sovateltide (an ETBR agonist) injected intravenously showed better survival and neurological and motor function improvement than control. Higher neuronal progenitor cells (NPCs) differentiation along with better mitochondrial morphology and biogenesis in the brain of sovateltide rats were noted. Exposure of cultured NPCs to hypoxia and sovateltide also showed higher NPC differentiation and maturation. This study shows a novel role of ETBR in NPCs and mitochondrial fate determination in cerebral ischemia, and in improving neurological deficit after stroke.

Role of endothelin B receptor in oligodendroglioma proliferation and survival: In vitro and in vivo evidence

In this study, the role of the endothelinB receptor (ETBR) in oligodendroglioma cell proliferation and survival was investigated invitro and invivo. The overexpression and knockdown of ETBR was conducted in Hs683 human oligodendroglioma cells, and cell proliferation and activation (phosphorylation) of extracellular signal-regulated kinase (ERK) were measured invitro. An orthotopic xenograft oligodendroglioma mouse model was established. Mouse survival times and immunohistochemical Ki67 staining in the xenografts were examined. Invitro experiments demonstrated that the overexpression of ETBR significantly enhanced the proliferation of oligodendroglioma cells and the activation of ERK compared with the controls, which was eliminated by the selective ETBR inhibitor BQ788 and ERK-specific inhibitor U0126, but not selective endothelinA receptor inhibitor BQ123. By contrast, the knockdown of endogenous ETBR markedly decreased oligodendroglioma cell proliferation and the activation of ERK compared with the controls. Overexpression of ETBR significantly increased immunohistochemical Ki67 staining in the Hs683 cell orthotopic xenograft and decreased animal survival. By contrast, knockdown of ETBR significantly decreased Ki67 staining and increased mouse survival times. Intratumoral injection of BQ788, but not BQ123, significantly decreased Ki67 staining and prolonged mouse survival times. In conclusion, ETBR was demonstrated to mediate the proliferation of oligodendroglioma cells according to an ERK-dependent mechanism. Using an orthotopic xenograft oligodendroglioma mouse model, it was demonstrated invivo that ETBR promotes oligodendroglioma proliferation and that the selective ETBR antagonist effectively inhibits the proliferation of oligodendroglioma cells and prolongs survival times. This study provides a novel insight into the role of ETBR in oligodendroglioma proliferation and survival, and provides the first invivo evidence that ETBR-specific antagonists are a potential therapeutic alternative for oligodendrogliomas.

Re-expression of the methylated EDNRB gene in oral squamous cell carcinoma attenuates cancer-induced pain

Endothelin-1 is a vasoactive peptide that activates both the endothelin A (ETA) and endothelin B (ETB) receptors, and is secreted in high concentrations in many different cancer environments. Although ETA receptor activation has an established nociceptive effect in cancer models, the role of ETB receptors on cancer pain is controversial. EDNRB, the gene encoding the ETB receptor, has been shown to be hypermethylated and transcriptionally silenced in many different cancers. In this study we demonstrate that EDNRB is heavily methylated in human oral squamous cell carcinoma lesions, which are painful, but not methylated in human oral dysplasia lesions, which are typically not painful. ETB mRNA expression is reduced in the human oral squamous cell carcinoma lesions as a consequence of EDNRB hypermethylation. Using a mouse cancer pain model, we show that ETB receptor re-expression attenuates cancer-induced pain. These findings identify EDNRB methylation as a novel regulatory mechanism in cancer-induced pain and suggest that demethylation therapy targeted at the cancer microenvironment has the potential to thwart pain-producing mechanisms at the source, thus freeing patients of systemic analgesic toxicity.

Role of endothelin-B receptors in the pulmonary circulation

Endothelin-1 (ET-1) is a potent vasoactive peptide and is thought to play an important role in the regulation of vascular tone. ET-1 can both constrict blood vessels, via endothelin-A (ET-A) receptors in vascular smooth muscle cells, and dilate then via endothelin-B (ET-B) receptors in endothelial cells in the systemic circulation. To determine the role of ET-B receptors in the pulmonary circulation, we examined the hemodynamic effects of a selective ET-B receptor agonist (IRL 1620) in rats. In rat lungs perfused with a salt solution, IRL 1620 caused pulmonary vasoconstriction in a dose-dependent manner. In lungs perfused with a hypoxic half-blood solution (10% O2), doses of IRL 1620 less than 10 nM caused pulmonary vasodilation, but higher doses caused pulmonary vasoconstriction. IRL 1620 caused transient vasodilation of the systemic circulation at every dose used (0.1, 1, and 5 nmol/kg) in anesthetized rats. In contrast, the effects of IRL 1620 on the pulmonary circulation varied with the dose. Small doses (0.1 or 1 nmol/kg) caused pulmonary vasodilation, but a higher dose (5 nmol/kg) caused pulmonary vasoconstriction. These results show tachyphylaxis in the pulmonary vasodilator response to IRL 1620, but not in the systemic vasodilator response. The present data show the dual action (vasoconstriction and vasodilation) of ET-B receptors.