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This Article Full Text Full Text (PDF) All Versions of this Article: 290/4/H1337    most recent 00936.2005v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (11) Citing Articles via Google Scholar Google Scholar Articles by Fetalvero, K. M. Articles by Martin, K. A. Search for Related Content PubMed PubMed Citation Articles by Fetalvero, K. M. Articles by Martin, K. A.

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Regulation of Cardiovascular Functions by Eicosanoids and Other Lipid Mediators

The prostacyclin receptor induces human vascular smooth muscle cell differentiation via the protein kinase A pathway

¹Department of Pharmacology and Toxicology, Dartmouth Medical School; and ²Department of Surgery, Section of Vascular Surgery, Dartmouth-Hitchcock Medical Center; and ³Department of Medicine, Section of Cardiology, Dartmouth Medical School, Lebanon, New Hampshire

Submitted 1 September 2005 ; accepted in final form 14 November 2005

Recent studies of cyclooxygenase-2 (COX-2) inhibitors suggest that the balance between thromboxane and prostacyclin is a critical factor in cardiovascular homeostasis. Disruption of prostacyclin signaling by genetic deletion of the receptor or by pharmacological inhibition of COX-2 is associated with increased atherosclerosis and restenosis after injury in animal models and adverse cardiovascular events in clinical trials (Vioxx). Human vascular smooth muscle cells (VSMC) in culture exhibit a dedifferentiated, migratory, proliferative phenotype, similar to what occurs after arterial injury. We report that the prostacyclin analog iloprost induces differentiation of VSMC from this synthetic, proliferative phenotype to a quiescent, contractile phenotype. Iloprost induced expression of smooth muscle (SM)-specific differentiation markers, including SM-myosin heavy chain, calponin, h-caldesmon, and SM -actin, as determined by Western blotting and RT-PCR analysis. Iloprost activated cAMP/protein kinase A (PKA) signaling in human VSMC, and the cell-permeable cAMP analog 8-bromo-cAMP mimicked the iloprost-induced differentiation. Both myristoylated PKA inhibitor amide-(14–22) (PKI, specific PKA inhibitor), as well as ablation of the catalytic subunits of PKA by small interfering RNA, opposed the upregulation of contractile markers induced by iloprost. These data suggest that iloprost modulates VSMC phenotype via G_s activation of the cAMP/PKA pathway. These studies reveal regulation of VSMC differentiation as a potential mechanism for the cardiovascular protective effects of prostacyclin. This provides important mechanistic insights into the induction of cardiovascular events with the use of selective COX-2 inhibitors.

iloprost; smooth muscle-specific differentiation markers; phenotypic modulation; signal transduction; intimal hyperplasia

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