Endothelins (ET) are highly potent vasoconstrictor proteins distributed throughout all areas of the body, and are implicated in a number of conditions and diseases.1 Members of the Endothelin family of peptides consist of Pre-pro-endothelin-1, a biologically inactive precursor form cleaved by furin covertase to produce Big Endothelin-1 (Big ET-1), which is cleaved again by endothelin converting enzyme (ECE) between Trp-21 and Val-22 to yield the active ET-1 (1-21).2 Alternatively, pulmonary chymase is also capable of generating ET-1 (1-31) by cleaving the Tyr31–Gly32 bond of big ET-1.2, 3 Isoforms include ET-2, ET-3, and ET-4.2 All have two disulfide bonds that hold them in a conical spiral shape.2 In addition to their vasoconstrictive properties, endothelins have inotropic and mitogenic properties.2 They influence salt and water balance, affect intracellular Ca2+ concentrations and signal transduction cascades, contract non-vascular smooth muscle, alter central and peripheral sympathetic activity, and stimulate the renin-angiotensin-aldosterone system.2-5
ETs are normally kept at stable levels in healthy individuals, but can become overexpressed, leading to high blood pressure, kidney disease, and numerous cardiovascular diseases such as pulmonary hypertension, cardiac hypertrophy, myocardial infarction, heart failure, and cerebral vasospasm.1, 2 ET disregulation is also a key component of tumorigenesis in several types of cancer.6
Fluorescently labeled endothelins have various applications in ET-related disease research. They are utilized as probes in visualizing intracellular processes and molecular interactions between ET-1 and potential ET-antagonists or inhibitors at the cellular level.7 They are also used for localizing and monitoring ECE activity and ET-receptor binding affinity via fluorescence fluctuation spectroscopy.8, 9 Specific ET isoform binding sites throughout the body may be studied using labeled ET. In addition, flow cytometry is used in combination with labeled ET to assay ET-receptor expression during different periods of the cell cycle,10 and in vivo and in vitro imaging of ET activity is capable with fluorescent ET.11 Overall, these unique peptides offer a wide range of approaches to further studying ET function and ET-related mechanisms.
1. Palma, BD. et al. Brazilian J. Med. Biol. Res. 35, 75 (2002).
2. Lüscher, T. Circulation 102, 2434 (2000).
3. Fecteau, M. et al. Hypertension 46, 87 (2005).
4. Inoue, A. et al. J. Biol. Chem. 264, 14954 (1989).
5. Highsmith, RF. et al. FASEB J. 9, 1196 (1995).
6. Smith, K. et al. Br. J. Cancer 88, 163 (2003).
7. Boese, G. et al. J. Cardiovasc. Pharmacol. 36, S44 (2000).
8. Heilker, R. et al. Biochem. 43, 9021 (2004).
9. Higuchi, K. et al. J. Biol. Chem. 266, 18352 (1991).
10. Kobayashi, S. et al. J. Biol. Chem. 273, 12584 (1998).
11. Clark, JC. et al. Br. J. Pharmacol. 159, 812 (2010).
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