Premium
Nitric oxide reduces vascular smooth muscle cell elastase activity through cGMP‐mediated suppression of ERK phosphorylation and AML1B nuclear partitioning
Author(s) -
Mitani Yoshihide,
Zaidi Syed H. E.,
Dufourcq Pascale,
Thompson Karen,
Rabinovitch Marlene
Publication year - 2000
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.14.5.805
Subject(s) - elastase , nitric oxide , mapk/erk pathway , phosphorylation , elastin , chemistry , protein kinase a , kinase , p38 mitogen activated protein kinases , vascular smooth muscle , nitric oxide synthase , microbiology and biotechnology , medicine , pharmacology , endocrinology , biochemistry , biology , enzyme , smooth muscle , pathology , organic chemistry
Nitric oxide (NO) reduces the severity of pulmonary vascular disease in rats as do elastase inhibitors. We therefore hypothesized that NO inhibits elastase by suppressing mitogen‐activated protein kinases that trans ‐activate AML1B, a transcription factor for elastase. We used cultured pulmonary artery smooth muscle cells in which serum‐treated elastin (STE) induces a > threefold increase in elastase activity as evaluated by solubilization of [ 3 H]‐elastin. NO donors (SNAP and DETA NONO‐ate) inhibited elastase in a dose‐dependent manner as did a cGMP mimetic (8‐pCPT‐cGMP). SNAP inhibition of elastase was reversed by coadministration of a cGMP‐PKG inhibitor (Rp‐8‐pCPT‐cGMP). The STE‐induced increase in phospho‐ERK was suppressed by NO donors and the cGMP mimetic, and reversed by cGMP‐PKG inhibitor, as was expression of AML1B and DNA binding in nuclear extracts. A concomitant increase in p38 phosphorylation was also inhibited by SNAP, but whereas MEK inhibitor (PD98059) suppressed elastase and AML1B‐DNA binding, a p38 inhibitor (SB202190) did not. Our study uniquely links NO with inhibition of elastase‐dependent matrix remodeling in vascular disease by suggesting a cGMP‐PKG‐related mechanism suppressing ERK‐mediated partitioning of AML1B in nuclear extracts.—Mitani, Y., Zaidi, S. H. E., Dufourcq, P., Thompson, K., Rabinovitch, M. Nitric oxide reduces vascular smooth muscle cell elastase activity through cGMP‐mediated suppression of ERK phosphorylation and AML1B nuclear partitioning. FASEB J. 14, 805–814 (2000)