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  • Gupta et al have shown that a genetic


    Gupta et al have shown that a genetic variant associated with the 5 vascular diseases (coronary artery disease, migraine, carotid artery dissection, fibro-muscular dysplasia, and hypertension) is a distal regulator of the ET-1 gene [30]. They found that a single nucleotide polymorphism (SNP) located within a noncoding DNA region of the PHACTR1 gene, called rs9349379, enhances the expression of the ET-1 gene [30], and also is the potential variant responsible for increased risk of coronary artery disease, and heart attacks from data collected from over 200,000 peoples [30]. The conversion from big ET-1 to ET-1 is essential for exertion of biological activity, since the pressor action of big ET-1 was almost completely inhibited by a relatively large dose of phosphoramidon [31,32]. ECE was purified from rat lung [33]. ECE cDNA was initially cloned from rat lung and bovine adrenal cortex cDNA libraries [34]. The structure of the ECE gene reflects about 760 Murine receptor metalloprotease enzyme, containing a single membrane-spanning sequence with only a N-terminal cytoplasmic tail and an extracellular C-terminal acid residues that contains the catalytic domain. Amino acid residues match the highly conserved consensus sequence of a zinc-binding motif, HEXXH, which is shared by many known metalloproteases. Northern blot analysis demonstrated a ubiquitous distribution of mRNA for this enzyme, with the highest expression in endothelium, lung, ovary, testis, and adrenal medulla [35]. This enzyme possesses more than 90% primary amino acid homology, and are termed ECE-1 [35]. They appear to be associated with the plasma membrane and Golgi complex and to process big ET-1 more efficiently than either big ET-2 or big ET-3. From bovine endothelial cell cDNA libraries, an ECE was cloned [36]. The enzyme termed ECE-2 is sensitive to phosphoramidon and converts big ET-1 more efficiently than big ET-2 or big ET-3, but exhibits the striking differences from ECE-1 in several points. Interestingly, Northern blot analysis revealed that neural tissues, such as cerebral cortex, cerebellum and adrenal medulla, show the highest expression of ECE-2 mRNA.
    Distribution of the mRNA/peptide in the cardiovascular system Southern blot analysis of human genomic DNA under low hybridization stringency with a 42-mer synthetic oligonucleotide probe corresponding to amino acid residues 7–20 of ET, showed that three different restriction fragments were always detected regardless of the restriction endonucleases used. The nucleotide sequences encoding amino acid residues of the three ETs are highly conserved among the three genes, with 77–82% of the nucleotide residues being identical [2]. By contrast, the nucleotide sequences upstream from the mature peptides are very poorly conserved. These observations suggest that although the three genes are evolutionally relatively distant from each other, the genes evolved from a common ancestral gene under strong pressure to preserve mature ET sequences. The three peptides were designated ET-1, ET-2 and ET-3 [5]. ET-1 is the original peptide corresponding to that detected in the culture medium of porcine aortic endothelial cells [1,2]. Although vascular endothelial cells are the major source of ET-1, Northern blot analysis revealed that the genes encoding the three ET isopeptides are expressed with different patterns in a wide variety of cell types including cardiac myocytes, vascular smooth muscle cells, pituitary cells, macrophages, and mast cells, suggesting that the peptides may participate independently in complex regulatory mechanisms in various organs. The conservation of numerous ET-related genes was also observed in several mammalian species examined, including human, pig, and rat. Further, four cardiotoxic peptides highly homologous to ETs, sarafotoxins (S6a-S6d), were isolated from the snake venom of Atractaspis engaddensis. ET-like immunoreactivity was also found in several species of invertebrates and fishes, indicating that ETs found in humans seem to have a long evolutionary history.