5 g, 2 g, 2 g plus HIF inhibitor U0126 (10(-5)M), 17-[2-(dimethylamino)ethyl] amino-17-desmethoxygeldanamycin (17-DMAG, 10(-5)M), or echinomycin (10(-6)M), or 2 g plus dimethyloxallyl glycine (DMOG; 10(-4)M), a prolyl-hydroxylase inhibitor that stabilizes HIF. The fold-change in PHE and KCl contraction was compared with the control contraction at 0.5-g tension for 1 hour. Vein tissue homogenates were analyzed for HIF-1 alpha, HIF-2 alpha, MMF-2, and MMP-9 messenger RNA (mRNA) and protein amount using real-time reverse transcription
polymerase chain reaction and Western blots.
Results: Compared with control IVC contraction at 0.5-g tension for 1 hour, the PHE and KCl contraction after prolonged 0.5-g tension was 2.0 +/- 0.35 and 1.1 +/- 0.06, respectively. Vein contraction to PHE and KCl after PRN1371 prolonged 2-g tension was significantly reduced (0.87 +/- 0.13 and 0.72 +/- 0.05, respectively). PHE-induced contraction was restored in IVC exposed to prolonged 2-g tension plus the HIF inhibitor SBI-0206965 chemical structure U0126 (1.38 +/- 0.15) or echinomycin (1.99 +/- 0.40). U0126 and echinomycin also restored KCl-induced contraction in NC exposed to prolonged 2-g tension (1.14 +/- 0.05 and 1.11 +/- 0.15, respectively). Treatment with DMOG further reduced PHE- and KCl-induced contraction in veins subjected to prolonged 2-g tension (0.47 +/- 0.06 and 0.57 +/- 0.01, respectively). HIF-1 alpha and HIF-2 alpha
inRNA were overexpressed in NC exposed to prolonged 2-g tension, and the overexpression was reversed by U0126. The overexpression of HIF-1 alpha and HIF-2 alpha in stretched NC was associated with increased MMP-2 and MMP-9 mRNA. The protein amount of HIf-1 alpha,
HIF-2 alpha, MMP-2, and MMP-9 was also increased in NC exposed to prolonged 2-g wall tension.
Conclusions:Prolonged increases in vein wall tension are associated with Selleck Fosbretabulin overexpression of HIF-1 alpha and HIF-2 alpha, increased MMP-2 and MMP-9 expression, and reduced venous contraction in rat IVC. Together with our report that MMP-2 and MMP-9 inhibit NC contraction, the data suggest that increased vein wall tension induces HIF overexpression and causes an increase in MMP expression and reduction of venous contraction, leading to progressive venous dilation and varicose vein formation. (J Vase Surg 2011;53:764-73.)”
“Midkine (MK), a neurotrophic factor with important roles in survival and differentiation of dopaminergic neurons, is upregulated in different brain areas after administration of different drugs of abuse suggesting MK could modulate drugs of abuse-induced pharmacological or neuroadaptative effects. To test this hypothesis, we have studied the effects of amphetamine administration in MK genetically deficient (MK-/-) and wild-type (MK+/+) mice. In conditioning studies, we found that amphetamine induces conditioned place preference (CPP) similarly in both MK-/- and MK+/+ mice.