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Epithelial Function and Airway Responsiveness
Published in Alastair G. Stewart, AIRWAY WALL REMODELLING in ASTHMA, 2020
Roy G. Goldie, Janet M. H. Preuss
It is well established that the endogenous peptide endothelin-1 (ET-1) is synthesised in vascular endothelial cells.95 However, it is also now established that the bronchial epithelium is a major site of synthesis and release of this peptide.96,97 ET-1 is a potent spasmogen in human bronchial smooth muscle,98,99 accelerates the growth of airway smooth muscle cells in culture100,101 and stimulates mucus gland secretion.102 These activities suggest a role for ET-1 in asthma, since elevated airway tone, airway smooth muscle hyperplasia, and hypersecretion of mucus are characteristic features of this disease.103 Immunoreactive ET has also been shown to be released from human bronchial,104 canine,105 and guinea pig106 tracheal epithelial cells. In addition, ET-like immunoreactivity can be demonstrated in bronchiolar epithelial cells in vivo in rats, and mice, as well as in mucus, serous, and Clara cells with very little observed in basal or ciliated cells.107 Importantly, levels of ET-like immunoreactive material are significantly elevated in the bronchial epithelium97 and bronchoalveolar lavage fluid of asthmatic individuals,108 a finding which may be of particular relevance to putative pathophysiological actions of this peptide.
Heart disease
Published in Catherine Nelson-Piercy, Handbook of Obstetric Medicine, 2020
PAH-targeted therapies should be continued in pregnancy. Specific therapies include: – Phosphodiesterase inhibitors (sildenafil, tadalafil). These can be safely continued or instigated in pregnancy.– Endothelin receptor antagonists (bosentan, ambrisentan). These are usually discontinued in pregnancy, as they are teratogenic in rats.– Prostanoid analogues (epoprostenol – intravenous [i.v.], iloprost – nebulized or i.v.) and nitric oxide – inhaled. These can be safely continued or instituted in pregnancy.
Endothelial cell dysfunction and pre-eclampsia
Published in Pankaj Desai, Pre-eclampsia, 2020
Many markers have been identified in experimental and clinical investigations, which are supposed to indicate the endothelial activation process. They have been reported in pre-eclampsia and include: Increased circulating concentration of endothelin-1.5Increased levels of fibronectin in circulation.6Decreased levels of circulating vasodilator PGI2.7Altered levels of circulating thrombomodulin.8
A pinitol-rich Glycyrrhiza glabra L. leaf extract as functional supplement with potential in the prevention of endothelial dysfunction through improving insulin signalling
Published in Archives of Physiology and Biochemistry, 2022
Laura Siracusa, Cristina Occhiuto, Maria Sofia Molonia, Francesco Cimino, Marco Palumbo, Antonella Saija, Antonio Speciale, Concetta Rocco, Giuseppe Ruberto, Mariateresa Cristani
IRS-1 protein phosphorylation is a determining factor for the insulin signal transduction. In physiological conditions, the binding of insulin to its membrane receptor (IR) triggers the autophosphorylation of tyrosine residues and leads to a series of phosphorylation cascade involving the activation of the IRS/PI3K/Akt/eNOS pathway. One of the most evident effects of insulin resistance is the impairment of the activation of this signalling pathway. This impairment leads to a decreased NO production and increased endothelin 1 (ET-1) secretion. High levels of circulating cytokines or FFAs cause drastic changes in insulin pathway and in particular induce IRS-1 phosphorylation at the serine site and inhibit IRS-1 tyrosine phosphorylation, thus blocking the PI3K/Akt/eNOS pathway with subsequent insulin resistance (Gual et al. 2005). In the current study, we investigated the effects of PA-induced insulin resistance by focussing on Tyr895 phosphorylation of IRS-1 protein as a key regulator step in insulin signal transduction. Figure 4 shows that insulin-induced phosphorylation at Tyr895 site of IRS-1 was negatively affected by the exposure of endothelial cells to PA. Both GGLME (in a dose-dependent way) and d-pinitol pre-treatments were associated to an increased Tyr895 phosphorylation of IRS-1. Finally, the treatment of GGLME or d-pinitol alone was associated to an increase of IRS-1 Tyr895 phosphorylation with respect to controls.
Selexipag for the treatment of pulmonary arterial hypertension
Published in Expert Review of Respiratory Medicine, 2021
Léon Genecand, Julie Wacker, Maurice Beghetti, Frédéric Lador
For the large majority of PAH patients, pulmonary vasoreactivity testing is negative, CCB are not useful and pulmonary vasodilator therapies should be tried. Imbalance between vasoconstrictors (thromboxane, endothelin) and vasodilators (nitric oxide, prostacyclin (PGI2)) is one of the various and complex physiopathological mechanism that leads to the development of PAH. Pulmonary vasodilators target three different pathways: 1) NO, 2) endothelin and 3) PGI2 [6]. NO is a pulmonary vasodilator that can be increased with phosphodiesterase-5 (PDE-5) inhibitors (sildenafil, tadalafil, and verdenafil) or guanylate cyclase stimulators (GCs) (riociguat). Endothelin is a pulmonary vasoconstrictor with mitogenic effects. Endothelin antagonists (bosentan, ambrisentan, macitentan) inhibit endogenous endothelin’s effects resulting in pulmonary vasodilatation. PGI2 have vasodilator, antiplatelet, and antiproliferative properties [7]. Synthetic PGI2 (Intravenous (IV) epoprostenol), PGI2 analogs (beraprost, iloprost, treprostinil), and PGI2 receptor agonist (selexipag) mimic the action of endogenous PGI2.
Secondhand cigarette smoke induces increased expression of contractile endothelin receptors in rat coronary arteries via a MEK1/2 sensitive mechanism
Published in Scandinavian Cardiovascular Journal, 2021
Lei Cao, Isak Lindstedt, Marie-Louise Edvinsson, Na-Na Ping, Yong-Xiao Cao, Lars Edvinsson
One type of “intermediate” risk factor are the endothelins. In fresh arteries the ETA receptor is expressed in the vascular smooth muscle cells while the ETB receptor is expressed in the endothelium, mediating relaxation [24]. In ischemic conditions we have observed a detrimental shift. The endothelial ETB receptor functions less well and the ETB mRNA that can be found in vascular smooth muscle produces contractile ETB receptors which potentiates the contractility of the elevated levels of ET-1 in ischemic conditions [25]. The endothelins have been associated with other risk factors for ischemic heart disease such as hypertension and atherosclerosis [26–28]. Furthermore, higher ET-1 levels have been independently associated both in prevalent and incident cohort data with coronary heart disease in humans, even after adjusting for smoking [29,30]. Also, enhanced risk of coronary heart disease was seen with increasing baseline ET-1 levels [30].