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The prostacyclin receptor induces human vascular smooth muscle cell differentiation via PKA
Author(s) -
Fetalvero Kristina M,
Shyu Maureen,
Nomikos Athena P,
Chiu YuhFang,
Wagner Robert J,
Powell Richard J,
Hwa John,
Martin Kathleen A
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a665-d
Subject(s) - iloprost , prostacyclin , vascular smooth muscle , calponin , endocrinology , phenotypic switching , medicine , microbiology and biotechnology , rhoa , biology , chemistry , signal transduction , actin , smooth muscle
Objective Disrupted prostacyclin signaling leads to increased atherosclerosis and restenosis in animal models, and adverse cardiovascular events in clinical trials (Vioxx®). Human vascular smooth muscle cells (VSMC) in culture exhibit a dedifferentiated phenotype, similar to that in arterial injury. We aimed to determine if the prostacyclin analog iloprost induces VSMC differentiation. Methods Human VSMC were isolated by explant from arteries from organ donors, or superficial femoral arteries following amputation and cultured in M199 with 10% FBS. VSMC in 2.5% FBS were exposed to 2.5 nM iloprost or vehicle for 2–24 hours. VSMC phenotype was assayed by cell area, immunoblotting or sqRT‐PCR for contractile markers of differentiation. siRNA was transduced by nucleofection. cAMP and PKA assays confirmed prostacyclin receptor signaling. Results Iloprost induced a differentiated morphology and expression of the smooth muscle differentiation markers myosin heavy chain, calponin, h‐caldesmon and α‐actin. Iloprost activated cAMP/PKA signaling, and 500 nM 8‐Br‐cAMP mimicked iloprost‐induced differentiation. Myristoylated‐PKI or siRNA knockdown of PKA opposed iloprost‐induced differentiation. Conclusions These data show that iloprost modulates VSMC phenotype via cAMP/PKA, suggest a novel mechanism for the cardioprotective effects of prostacyclin, and provide further insights into the cardiovascular events seen with selective COX‐2 inhibitors. This work was supported by grants from the NIH NHLBI and an NIH NCI training grant