Endothelin Synthesis

Endothelin (ET) exerts diverse effects in lung tissue, including smooth muscle cell proliferation, pulmonary vasoconstriction, mucus secretion, DNA synthesis stimulation, and modulation of vascular permeability. ET is synthesized through a multistep process beginning with transcription of the preproendothelin (PPET) gene into mRNA. This transcription is regulated by several transcription factors, including c-Fos, c-Jun, NF-1, AP-1, and GATA-2.

The translated PPET peptide undergoes post-translational cleavage by furin-like endopeptidases at dibasic sites to form proendothelin, which is then processed into big endothelin, an inactive intermediate. Finally, specific proteolytic cleavage generates the active ET isoforms: ET-1 and ET-2 at the Trp-Val site, and ET-3 at the Trp-Ile site, along with detectable carboxy-terminal fragments.

ET-1 synthesis is further regulated by intracellular signaling pathways: protein kinase C activates trans-acting transcription factors FOS and JUN, while TGF-β induces PPET-1 mRNA via NF-1 binding elements. This tightly controlled multi-step process ensures precise regulation of ET levels, which is crucial for vascular homeostasis and pulmonary function.