Since the vessels were obtained from severely diseased patients the current data may suggest that there is activation of all three major MAPKs in advanced cardiovascular disease

Since the vessels were obtained from severely diseased patients the current data may suggest that there is activation of all three major MAPKs in advanced cardiovascular disease. Clinical relevance Endothelin induces strong vasoconstriction in human blood vessels and endothelin receptors are up-regulated in cardiovascular disease such as hypertension, arteriosclerosis and myocardial infarction. 6c contraction, endothelin ETB receptor protein and mRNA expression levels were increased after organ culture. This increase was antagonized by; (1) PKC inhibitors (10 M bisindolylmaleimide I and 10 M Ro-32-0432), and (2) inhibitors of the Torcetrapib (CP-529414) p38, extracellular signal related kinases 1 and 2 (ERK1/2) and C-jun terminal kinase (JNK) MAPK pathways (10 M SB203580, 10 M PD98059 and 10 M SP600125, respectively). Conclusion In conclusion, PKC and MAPK seem to be involved in the up-regulation of endothelin ETB receptor expression in human internal mammary arteries. Inhibiting these intracellular signal transduction pathways may provide a future therapeutic target for hindering the development of vascular endothelin ETB receptor changes in cardiovascular disease. Background Endothelin-1 is a potent vasoconstrictor produced by endothelial cells. It is a vasoactive agent that mediates multiple vascular actions and plays an important role in hypertension and cardiovascular diseases by promoting changes in vascular reactivity and endothelial function, cardiovascular fibrosis, tissue remodeling, inflammation, and oxidative stress. Torcetrapib (CP-529414) Endothelin exerts its effect through two different G protein coupled receptors, the endothelin type A (ETA) receptor and the endothelin type B (ETB) receptor [1-3]. The endothelin ETA receptors are expressed in vascular smooth muscle cells and mediate vasoconstriction. In healthy conditions, endothelin ETB receptors are mainly located on endothelial cells and mediate vasodilatation via the release of nitric oxide, prostaglandins Torcetrapib (CP-529414) and endothelium-derived hyperpolarizing factor Torcetrapib (CP-529414) [4-6]. However, endothelin ETB receptors on vascular smooth muscle cells have been observed to be upregulated during pathological conditions such as atherosclerosis [7], congestive heart failure [8], ischemic heart disease [9] and hypertension [10]. Endothelin receptors on vascular smooth muscle cells are both mitogenic, leading to atherosclerosis, and mediate strong vasoconstriction which may lead to elevated vascular tone frequently observed in cardiovascular disease. Endothelin receptor regulation can be studied in detail, ex vivo, using organ culture of intact arteries. Endothelin ETB receptors on smooth muscle cells are up-regulated when whole blood vessels are incubated for 12 to 48 hours [11]. Furthermore, endothelin ETB receptors are up-regulated in human coronary arteries after organ culture, in a similar way as in ischemic heart disease in man [12]. Endothelin receptor-changes also occur during organ culture in rat cerebral and peripheral arteries, mimicking that observed in peripheral artery disease, stroke and subarachnoidal haemorrhage [13-15]. Detailed delineation of the regulation of vascular endothelin receptors can be performed by culture in the presence of different humoral factors or intracellular signal transduction pathway inhibitors. We aim to identify the intracellular signal transduction pathways Rabbit polyclonal to Cannabinoid R2 that regulate the expression of endothelin receptors in the vasculature. These may provide future therapeutic targets for hindering the development of vascular endothelin receptor changes in cardiovascular disease. In a previous study, culture of porcine coronary arteries shows that protein kinase C (PKC) and mitogen activated protein kinases (MAPKs) are signaling pathways that regulate endothelin receptor expression [16]. Other studies, using rat cerebral arteries, show similar results [17,18]. Hitherto, the regulation of endothelin receptors have mainly been studied in animals and data from humans barely exists. When identifying new targets for pharmaceutical intervention, it is of importance that the research is performed not only in animals, but also in patients. In the present study, internal mammary arteries from patients undergoing coronary artery bypass graft surgery were studied to examine the role of PKC and MAPK in the endothelin ETA and ETB receptor regulation in humans. PKC.