Implications of the molecular basis of prostacyclin biosynthesis and signaling in pharmaceutical designs.
Prostacyclin (PGI(2)) is one of the major vascular protectors against thrombosis and vasoconstriction, caused by thromboxane A(2). Understanding the molecular mechanisms of PGI(2) biosynthesis and signaling is crucial to the development of therapeutic approaches to regulate PGI(2) functions. This review provides information regarding the most current advances in the findings of the molecular mechanisms for PGI(2) biosynthesis in the endoplasmic reticulum (ER) membrane through the coordination between PGI(2) synthase and its upstream enzymes, cyclooxygenase-1 (COX-1) or -2 (COX-2), and for PGI(2) signaling through its cell membrane receptors and nuclear peroxisome proliferator-activated receptors. The substrate presentation from the COXs to PGI(2) synthase and its cell membrane receptor/G protein coupling sites, as characterized by our group, are discussed in detail. The association between the regulation of the biosynthesis and signaling of PGI(2) with the pathophysiological processes of PGI(2)-related diseases is also discussed. The molecular knowledge of PGI(2) biosynthesis and signaling will help to design the next generation of drugs, specifically targeting the regulation of PGI(2) functions, which will undoubtedly provide advances in cardiovascular protection and the treatment of PGI(2)-related diseases.
Ruan
Ke-He
KH
The Vascular Biology Research Center, Division of Hematology, Department of Internal Medicine, University of Texas Health Science Center at Houston, 77030, USA. kruan@uth.tmc.edu
Dogné
Jean-Michel
JM
D000818:Animals; D019440:Anti-Obesity Agents / Q000494:pharmacology; D000959:Antihypertensive Agents / Q000627:therapeutic use; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D015195:Drug Design; D004717:Endometrium / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D011464:Epoprostenol / Q000031:analogs & derivatives* / Q000096:biosynthesis* / Q000627:therapeutic use; D005260:Female; D041981:Gastrointestinal Tract / Q000378:metabolism; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy; D007425:Intracellular Membranes / Q000378:metabolism; D019746:Intramolecular Oxidoreductases / Q000378:metabolism; D047492:Peroxisome Proliferator-Activated Receptors / Q000187:drug effects / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D044006:Receptors, Epoprostenol / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction
D019440:Anti-Obesity Agents; D000959:Antihypertensive Agents; D047492:Peroxisome Proliferator-Activated Receptors; D044006:Receptors, Epoprostenol; D003577:Cytochrome P-450 Enzyme System; D011464:Epoprostenol; D011451:Prostaglandin-Endoperoxide Synthases; D019746:Intramolecular Oxidoreductases; C022461:prostacyclin synthetase