In addition to vasoconstrictor actions acute effects ET exer

In addition to vasoconstrictor actions (acute effects), ET-1 exerts potent mitogenic actions on vascular smooth muscle cells and cardiac myocytes (chronic effects), hence causing vascular and cardiac hypertrophy [19,24,25]. These effects are mediated via stimulation of either ETA or ETB receptors, and might be provoked through sequential activation of intracellular kinase cascade, including raf-1, mitogen-activated protein kinase (MAPK) kinase, MAPK, and S6 kinase [5].
Pathophysiology of endothelin in the cardiovascular systems
Conclusions ET-1 shows a wide variety of biological effects, including contraction of nonvascular smooth muscle (intestinal, tracheal, broncheal, mesangial, bladder, uterine, and prostatic smooth muscle), stimulation of neuropeptides, pituitary hormone and atrial natriuretic peptide release and contain biosynthesis, modulation of neurotransmitter release, and increase of bone resorption. Furthermore, ET-1 has mitogenic properties, and causes proliferation and hypertrophy of a number of cell types, including vascular smooth muscle cells, cardiac myocytes, mesangial cells, bronchial smooth muscle cells and fibroblasts. ET-1 also induces the expression of several protooncogenes (c-fos, c-jun, c-myc, etc.). These actions are of potential significance in pathophysiological conditions associated with long-term changes in cardiovascular tissues, e.g. chronic heart failure, renal diseases hypertension, cerebral vasospasm, pulmonary hypertension. Currently, orally active ET receptor antagonists such as bosentan, ambrisentan, macitentan are clinically applied to the patients with pulmonary hypertension [5,78,80]. The concept of the cardiovascular continuum and AII was provides by Dzau et al. [191]. As for ET, we illustrate the concept of the cardiovascular disease continuum and the target diseases of the ET receptor antagonists as the Fig. 2. ET-1 is also deeply concerned with cardiac diseases, including cardiac hypertrophy, acute and chronic heart failure, etc [5,78,80,89,90]. Endogenous ET-1 is considered to be involved in progression of atheroscrelosis, hypertension, angina pectoris, myocardial infarction, heart failure, and pulmonary hypertension, and these diseases may become target diseases of the ET receptor antagonists (Fig. 2).
Conflict of interest
Acknowledgement This work was supported by the grant from the University of Tsukuba Project Research.
Introduction The Endothelin (ET) family consists of three isopeptides named ET-1, ET-2 and ET-3, which are produced by endothelial and several epithelial cell types, playing a relevant role in cancer biology by intervening and regulating many processes such as aberrant proliferation, escape from apoptosis and angiogenesis (Levin, 1995, Nelson et al, 2003). All these effects are obtained by linking of endothelins with distinct G protein-coupled receptors ETAR and ETBR which act in opposite manner and induce divergent intracellular effects (Simonson and Dunn, 1990). In particular, ET-1 has a high affinity to ETAR and through this linking can trigger many biological mechanisms such as modulating cell behaviour and local microenvironment homeostasis (Bhalla et al., 2009); yet, the most important role played by the ET axis seems connected to neoplastic transformation and tumour progression (Nakamuta et al., 1993). In fact, ET-1 can stimulate DNA synthesis promoting cell proliferation, it can alter the connexin expression by interfering with cell communication disrupting the intercellular gap junction (Spinella et al., 2003), and it is involved in neoangiogenesis through complex interaction with Vascular Endothelial Growth Factor (VEGF) synthesis (Wulfing et al., 2004). Elevated expression of ET-1 and ETAR has been correlated with poor tumour cell differentiation, increase of microvascular density, incidence of metastasis and reduced disease-free survival time in human breast cancer (Wulfing et al, 2003, Wulfing et al, 2004). Moreover, ETAR antagonists are successfully used in a number of human anticancer therapy protocols (Bagnato, Natali, 2004, Kandalaft et al, 2009).