Vein graft thrombi, a niche for smooth muscle cell colonization - a hypothesis to explain the asymmetry of intimal hyperplasia.

UNLABELLED: Essentials Vein graft failure is the most frequent late onset complication of coronary artery bypass grafting. Cuff technique-based interposition mouse model including new anticoagulation regime was conducted. Early vein graft thrombi may serve as a niche for smooth muscle cell colonization. The focal character of early thrombi may form the basis for the asymmetry of intimal hyperplasia. SUMMARY: Background Autologous saphenous veins are widely used in coronary artery bypass grafting; however, 10 years after surgery, 40% of grafts are completely occluded, and another 30% show reduced blood flow. Objective In the past, the central processes and signaling pathways responsible for this loss of patency have been identified. However, one central finding in the process of graft failure is so far not understood: the asymmetric character of intimal hyperplasia. It was the goal of the present study to address this aspect. Methods By the use of a cuff technique-based vein interposition mouse model with a new anticoagulation regime, alterations in vein grafts were analyzed 1 h, 1 day, 2 days, 3 days, 7 days and 21 days after reperfusion by means of immunolabeling, histochemistry, and high-resolution ultrasound. Results The novel and major finding of this study is that the vein graft thrombus may serve as a niche that is infiltrated and colonized by smooth muscle cells (SMCs). Fibroblast growth factor-1 and platelet-derived growth factor-B may be the SMC-attracting factors in the thrombus. The focal character of early thrombi may define the focal and asymmetric character of vein graft intimal hyperplasia. Conclusions Inhibiting the formation and reducing the size of early thrombi is an old concept for reducing vein graft failure. However, in light of the present new findings obtained under a clinic-like anticoagulation regime, early vein graft thrombus prevention/size reduction should be revisited in the prevention of graft failure.

Binding of NF-kB to the HIV-1 LTR is not sufficient to induce HIV-1 LTR activity.

Human immunodeficiency virus type 1 (HIV-1) spends a significant part of its life cycle as latent provirus in nonactivated cells. It induction requires mitogen stimulation. TPA treatment induces HIV-1 transcription by protein kinase C (PKC)-mediated activation of the cellular transcription factor NF-kB. PKC activation induces the dissociation of NF-kB from its inhibitor protein (IkB). The liberated NF-kB then binds to its proviral recognition sequence in the HIV-1 long terminal repeat (LTR) sequence. This step, however, is not sufficient to augment transcription. We demonstrate that NF-kB-mediated HIV-1 LTR activation is regulated by an additional event that is not dependent on IkB. A further phosphorylation event is proposed, since this step could be blocked by an inhibitor of a phospholipase C (PLC) type reaction. This inhibitor precludes the formation of diacylglycerols, which are required for activation of PKC isoenzymes. As an alternative pathway that is not dependent on PLC reactions, high-level transcription from the HIV-1 LTR is shown to require binding of both NF-kB and TAT.

Inhibition of c-fos transcription and phosphorylation of the serum response factor by an inhibitor of phospholipase C-type reactions.

Phospholipase C activity is necessary for transcriptional c-fos activation by providing diacylglycerol as an activator of protein kinase C. We found that transcriptional activation of c-fos and the phosphorylation of its major transcription factor were inhibited by tricyclodecan-9-yl xanthogenate, which blocks phospholipase C-type reactions. Transcription of the c-ras and beta-actin genes in the same cells remained unaffected.

Interruption of growth signal transduction by an antiviral and antitumoral xanthate compound.

The binding of growth factors to the cellular receptors elicits the phosphorylation of proteins which transmit growth signals to the nucleus [E. Rozengurt (1986) Science 234, 161-166]. Both the tyrosine-specific kinase (growth factor receptor) and the threonine-serine phosphorylating protein kinase C (pkC) become activated upon binding of the epidermal growth factor (EGF) to its receptor. Here we describe the selective inhibition of the pkC activation by tricyclodecane-9-yl-xanthogenate (D609) in the presence of unsuppressed receptor tyrosine autophosphorylation. As a consequence the affinity of EGF to the receptor was not down-regulated and the complex failed to be internalized.

Synergistic antiviral effect of xanthates and ionic detergents.

Xanthate compounds have been shown to exhibit antiviral activity against various DNA and RNA viruses under acidic pH conditions. It is now possible to utilize the unique broad range antiviral spectrum of these compounds under physiological pH conditions (pH 7.4) by simultaneous administration of certain ionic detergents. When used in conjunction with tricyclodecan-9-yl-xanthate (D609), sodium deoxycholate, sodium dodecylsulfate and certain fatty acids, which have no antiviral activity of their own, inhibit the replication of various DNA and RNA viruses (such as herpes simplex, vesicular stomatitis and Coxsackie B 4) in vitro at pH 7.4. Among saturated fatty acids of various chain lengths there was a marked size restriction in that the efficiency of undecanoic acid (11 C atoms) was three orders of magnitude greater than that of shorter (6 C atoms) or longer (18 C atoms) monocarbonic acids. Dose-response kinetics revealed a synergistic interaction between the xanthate and the monocarbonic acid. A dose that inhibited the replication of herpesvirus by a factor of 1000 still permitted mitotic activity in uninfected growing control cultures.