P171	Biomechanical stress induces tissue factor expression in vascular smooth muscle cells via RhoA/Rho-Kinase: inhibition by atorvastatin.
U.Bavendiek, J.Kumaravelu, M.Feurer, R.Ebensperger, K.Grote, B.Schieffer
Dept. of Cardiology & Angiology, Hannover Medical School, Hannover, DE.

Background: Arterial hypertension is a major risk factor of cardiovascular events in which the potent procoagulant tissue factor (TF) may be involved. Biomechanical vascular stress (e. g. in arterial hypertension) is known to activate small GTPases like RhoA while HMG-CoA-reductase inhibitors inhibit the activation of small GTPases via pleiotropic effects. Therefore, we assessed whether biomechanical stress induces the expression of TF in human vascular smooth muscle cells (SMC), mediated via the RhoA/Rho-kinase signaling pathway and blocked by the HMG-CoA-reductase inhibitor atorvastatin. Methods and Results: Mechanical stretch (cyclic strain, 15 % elongation, 0.5 Hz, Flexercell Strain Unit) induced the mRNA-expression (max. 3 h, n=4, p<0.001) and protein expression (westernblot, immunhistochemistry, max. 6 h, n=5) of TF in SMC. As stretch strongly induced the activation of RhoA in SMC (max. 30 min., RhoA activation assay, n=3) involvement of the downstream effector of RhoA, Rho-kinase, in the stretch induced expression of TF was investigated. Specific inhibtion of Rho-kinase with Y-27632 (10 µM) resulted in a marked reduction of the stretch induced TF expression (n=3). Furthermore pretreatment of SMC with atorvastatin (10 µM) inhibited the stretch induced activation of RhoA and expression of TF in SMC (n=3). Conclusion: Biomechanical stress induces the expression of tissue factor in vascular smooth muscle cells via RhoA/Rho-Kinase, demonstrating a potential pathomechanism explaining the increased rate of cardiovascular events in patients with arterial hypertension. Atorvastatin attenuates the stretch-induced expression of tissue factor by inhibition of RhoA, representing another beneficial pleiotropic effect of statins probably lowering atherothrombotic events in patients with arterial hypertension.

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