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1 Department of Pharmacology, Rush Presbyterian St. Luke's Medical Center, Chicago, IL, USA
* To whom correspondence should be addressed. E-mail: fei_huang{at}rush.edu.
Much evidence indicates that cAMP-dependent protein kinase (PKA) prevents increased endothelial permeability in response to inflammatory mediators. We investigated the hypothesis that PKA inhibits Rho GTPases, which are regulator proteins believed to mediate endothelial barrier dysfunction. Stimulation of human microvascular endothelial cells (HMEC) with thrombin (10 nM) increased activated RhoA (RhoA-GTP) within 1 min, which remained elevated ~4-fold over control for 15 min. The activation was accompanied by RhoA translocation to the cell membrane. However, thrombin did not activate Cdc42 or Rac1 within similar time points, indicating selectivity of activation responses by Rho GTPases. Pretreatment of HMEC with 10 µM forskolin plus 1 µM IBMX (3-isobutyl-1-methylxanthine) (FI) to elevate intracellular cAMP levels inhibited both thrombin-induced RhoA activation and translocation responses. FI additionally inhibited thrombin-mediated dissociation of RhoA from GDI (guanine nucleotide dissociation inhibitor) and enhanced in vivo incorporation of 32P by GDI. HMEC pretreated in parallel with FI showed >50% reduction in time for the thrombin-mediated resistance drop to return to near baseline and inhibition of ~23% of the extent of resistance drop. Infection of HMEC with replication-deficient adenovirus containing the PKI gene (PKA inhibitor) blocked both the FI-mediated protective effects on RhoA activation and resistance changes. In conclusion, the results indicate that PKA inhibited RhoA activation in endothelial cells, supporting a signaling mechanism of protection against vascular endothelial barrier dysfunction.
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