Urocortin 2: will a drug targeting both the vasculature and the right ventricle be the future of pulmonary hypertension therapy?
Urocortin 2: will a drug targeting both the vasculature and the right ventricle be the future of pulmonary hypertension therapy?
复制标题
尿皮质素 2：同时针对脉管系统和右心室的药物会成为肺动脉高压治疗的未来吗？
DOI：
10.1093/cvr/cvy117
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发表时间：
2018
影响因子：
10.8
通讯作者：
Graham,BrianB
中科院分区：
文献类型：
--
作者：
Stenmark,KurtR;Graham,BrianB
Pulmonary hypertension (PH) is characterized by vasoconstriction and abnormal remodelling of pulmonary vessels, leading to a progressive increase in pulmonary artery pressure and vascular stiffness, culminating in right ventricular (RV) failure and death. Currently available treatments for PH were developed to impair or restore an imbalance of vasoactive factors, arising as a result of endothelial and smooth muscle cell (SMC) dysfunction, and primarily function by vasodilation. These medications prolong life but the mortality remains unacceptably high. 1 A challenge for the field is identifying novel drug targets that can reverse the vascular structural changes and improve RV failure. The urocortins are in the corticotropin-releasing factor (CRF) family of proteins. This family includes CRF itself, urotensin 1, and urocortins 1 through 3 (Ucn1, Ucn2, and Ucn3). The urocortins are at measurable concentrations in human plasma at relatively high concentrations. All of these CRF family ligands have structural similarities and share an affinity for the CRF receptors, of which there are two subtypes: CRF-R1 and CRF-R2. 2–4 The specificity for ligand–receptor interactions is regulated by anatomic distribution of the ligands and receptors, variable receptor activity for different ligands, and transcriptional regulation of both ligands and receptors. Ucn1, Ucn2, and Ucn3 are all present in the central nervous system, heart, peripheral blood vessels, adrenal glands, skin, and skeletal muscle. In the heart, all three urocortin isoforms are present in all four chambers, although the expression is highest in the left ventricle; the primary receptor present in the heart is CRF-R2, in both myocytes and the coronary vascular network. In the peripheral vasculature, CRFR2 is present in arteries and veins, and in both vascular SMCs and endothelial cells. 2–5 Ucn1 signals through CRF-R2 preferentially, with a 10-to 50-fold higher affinity, but can also signal through CRF-R1; urocortins 2 and 3 exclusively signal via CRF-R2. Notably, both the urocortins and their receptors are often seen in the same cell within the cardiovascular system, implying paracrine or autocrine signalling functions. The urocortins and its receptors are also expressed by macrophages. 6 Cardiovascular expression of CRF-R2 is regulated by the urocortin ligands directly, as well as cortisol, adrenal corticotropic hormone, interleukins 1o and 6, tumour necrosis factor-o, and lipopolysaccharide. 7 The role of the Ucns in the systemic circulation has been studied. Systemic administration of Ucn1 or 2 results in vasodilation and reduced blood pressure, an effect mediated predominantly via CRF-R2 binding in SMCs with activation of adenylcyclase and cAMP accumulation. 8 Ucn1 also has endothelial-dependent vasodilatory effects involving nitric oxide (NO) and other mediators, and the Ucns may modulate neurohumoral systems including angiotensin-2 and endothelin-1 (ET-1). Ucns also have anti-trophic and anti-proliferative effects on cultured endothelial cells. Ucns have a less clear role in inflammation. Ucn1 can activate nuclear factor-kb (NFkb) and increase the expression of cyclooxygenase 2 and cytosolic lipase A2, but Ucns can also block TNFo and other cytokines being released from macrophages and prevent macrophage apoptosis. 9, 10 These complex, sometimes contradictory, results suggest the function of Ucns may depend on key factors including the type of the receptor present, systemic vs. local activation, species, and cell-type specificity. Overall, the weight of evidence generally favours an endothelial protective role for the Ucns in most cardiovascular pathologies. In the heart, the Ucns have direct CRF-R2 …
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DOI：
10.1210/endo.141.7.7572
发表时间：
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期刊：
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影响因子：
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作者：
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DOI：
10.1084/jem.20161924
发表时间：
2017-07-03
期刊：
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影响因子：
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作者：
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