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Role of Exchange Protein Directly Activated by cAMP‐1 (Epac‐1) in Pulmonary Artery Smooth Muscle Cells: A New Target for Pulmonary Hypertension
Author(s) -
Murray Fiona,
Suda Ryan Y.S.,
Do Thao,
Yokoyama Utako,
Thistlethwaite Patricia A.,
Yuan Jason XY,
Insel Paul A.
Publication year - 2008
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.22.1_supplement.1209.16
Subject(s) - guanine nucleotide exchange factor , gq alpha subunit , effector , pulmonary artery , medicine , chemistry , smooth muscle , endocrinology , pulmonary hypertension , signal transduction , gene isoform , microbiology and biotechnology , g protein , biology , gene , biochemistry
Dysfunctional cAMP signaling contributes to enhanced proliferation of pulmonary arterial smooth muscle cells (PASMC) in pulmonary arterial hypertension (PAH). Exchange protein directly activated by cAMP (Epac, Epac‐1 and Epac‐2 are isoforms), a guanine nucleotide exchange factor for Rap, has been identified as a cAMP‐effector. We found that PASMC isolated from PAH‐patients have decreased mRNA and protein expression of Epac‐1, decreased Rap‐1 activation and blunted anti‐proliferative response to an Epac‐selective cAMP analog [8‐pCPT‐2Me‐cAMP (8Me), 50μM, 24 hr]. Hypothesizing that increasing Epac‐1 expression in PAH‐PASMC would enhance the anti‐proliferative effect of cAMP, we restored its expression using an Epac‐1 adenovirus. Adv‐Epac‐1 increased Epac‐1 protein expression in PAH‐PASMC 20‐fold compared to Adv‐Lac‐Z without altering Epac‐2 and decreased serum‐induced proliferation more in PAH‐ than control‐PASMC (64 ± 2.8% and 38.3 ± 1.7% respectively, compared to Adv‐Lac‐Z). Over‐expression of Epac‐1 enhanced the anti‐proliferative effect of 8Me in PAH‐PASMC by 22.3±2.9% and increased Rap‐1 activation to a level similar to control‐PASMC. We conclude that decreased Epac‐1 contributes to altered signaling and increased PASMC proliferation in PAH. Restoring Epac‐1 expression may be beneficial in PAH by enhancing the effectiveness of drugs that increase cAMP. Supported by NIH and ALA.