8,9-Epoxyeicosatrienoic acid analog protects pulmonary artery smooth muscle cells from apoptosis via ROCK pathway

• Published in: Experimental cell research Vol. 316; no. 14; pp. 2340 - 2353
• Main Authors: Ma, Jun, Zhang, Lei, Li, Shanshan, Liu, Shulin, Ma, Cui, Li, Weiyang, Falck, J.R., Manthati, Vijay L., Reddy, D. Sudarshan, Medhora, Meetha, Jacobs, Elizabeth R., Zhu, Daling
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15-08-2010; Elsevier BV
• Subjects: 60 APPLIED LIFE SCIENCES; 8,11,14-Eicosatrienoic Acid - analogs & derivatives; 8,11,14-Eicosatrienoic Acid - chemistry; 8,11,14-Eicosatrienoic Acid - pharmacology; 8,9-EET; 8,9-EET analog; Acids; Animals; APOPTOSIS; Apoptosis - drug effects; ARACHIDONIC ACID; ARTERIES; Biochemistry; Blotting, Western; Catalysis; Cell Survival - drug effects; Cells, Cultured; Cellular biology; DEPOLARIZATION; DODECANOIC ACID; EPOXIDES; INHIBITION; Male; METABOLITES; MITOCHONDRIA; Molecular Structure; MUSCLES; Myocytes, Smooth Muscle - drug effects; PASMCs; Pulmonary Artery - cytology; Pulmonary Artery - drug effects; Rats; Rats, Wistar; Reverse Transcriptase Polymerase Chain Reaction; rho-Associated Kinases - metabolism; Rho-kinase; Signal Transduction - drug effects; Vasodilator Agents - chemistry; Vasodilator Agents - pharmacology; PAECs; SD; ROCK; PASMCs; 8,9-EET; 8,9-EET analog; Rho-kinase; apoptosis; EETs; AUDA
• ISSN: 0014-4827; 1090-2422
• DOI: 10.1016/j.yexcr.2010.05.013

Epoxyeicosatrienoic acids (EETs), metabolites of arachidonic acid (AA) catalyzed by cytochrome P450 (CYP), have many essential biologic roles in the cardiovascular system including inhibition of apoptosis in cardiomyocytes. In the present study, we tested the potential of 8,9-EET and derivatives to protect pulmonary artery smooth muscle cells (PASMCs) from starvation induced apoptosis. We found 8,9-epoxy-eicos-11(
Z)-enoic acid (8,9-EET analog (214)), but not 8,9-EET, increased cell viability, decreased activation of caspase-3 and caspase-9, and decreased TUNEL-positive cells or nuclear condensation induced by serum deprivation (SD) in PASMCs. These effects were reversed after blocking the Rho-kinase (ROCK) pathway with Y-27632 or HA-1077. Therefore, 8,9-EET analog (214) protects PASMC from serum deprivation-induced apoptosis, mediated at least in part via the ROCK pathway. Serum deprivation of PASMCs resulted in mitochondrial membrane depolarization, decreased expression of Bcl-2 and enhanced expression of Bax, all effects were reversed by 8,9-EET analog (214) in a ROCK dependent manner. Because 8,9-EET and not the 8,9-EET analog (214) protects pulmonary artery endothelial cells (PAECs), these observations suggest the potential to differentially promote apoptosis or survival with 8,9-EET or analogs in pulmonary arteries.