Smooth muscle cells in porcine vein graft intimal hyperplasia are derived from the local vessel wall.

BACKGROUND: Accelerated intimal hyperplasia (IH) is an important cause of morbidity and mortality in patients with atherosclerotic vascular disease treated with bypass vein grafts. We used an interposition vein graft model to determine the source of neointimal cells in a clinically relevant large animal model. METHODS: Jugular vein segments from sex-mismatched, MHC-in-bred pigs were implanted into common carotid arteries bilaterally and harvested up to 8 weeks postsurgery for stereological, histological, and immunofluorescence analyses. RESULTS: Progressive IH lesions contained macrophages and smooth muscle cells (SMC). Fluorescent in situ hybridization following grafting of female veins into male arteries revealed that only ∼10% of the SMC were male, confirming that the majority of intimal SMC derived from the local vessel wall. CONCLUSIONS: The majority of neointimal SMC in the IH seen after interposition vein grafting derive from the engrafted local vessel wall. These are the first results from a clinically relevant large animal model that confirm data from rodent models. They have implications for the utility of therapeutic stem cells in this type of intimal hyperplasia.

Therapeutics of vein graft intimal hyperplasia: 100 years on.

Intimal hyperplasia is central to the pathology of vein graft re-stenosis, and despite considerable advances in our understanding of vascular biology since it was first described 100 years ago, it is still a significant clinical problem. Recent decades have seen the development of many new therapeutic agents aimed at treating this condition, but the successes of laboratory studies have not been replicated in the clinic yet. This review discusses these therapeutic agents, how their modes of action relate to the pathogenesis of vein graft intimal hyperplasia, and considerations of ways in which such therapy may be improved in the future.

The double lysine motif of tapasin is a retrieval signal for retention of unstable MHC class I molecules in the endoplasmic reticulum.

Tapasin (tpn), an essential component of the MHC class I (MHC I) loading complex, has a canonical double lysine motif acting as a retrieval signal, which mediates retrograde transport of escaped endoplasmic reticulum (ER) proteins from the Golgi back to the ER. In this study, we mutated tpn with a substitution of the double lysine motif to double alanine (GFP-tpn-aa). This mutation abolished interaction with the coatomer protein complex I coatomer and resulted in accumulation of GFP-tpn-aa in the Golgi compartment, suggesting that the double lysine is important for the retrograde transport of tpn from late secretory compartments to the ER. In association with the increased Golgi distribution, the amount of MHC I exported from the ER to the surface was increased in 721.220 cells transfected with GFP-tpn-aa. However, the expressed MHC I were less stable and had increased turnover rate. Our results suggest that tpn with intact double lysine retrieval signal regulates retrograde transport of unstable MHC I molecules from the Golgi back to the ER to control the quality of MHC I Ag presentation.

Association of tapasin and COPI provides a mechanism for the retrograde transport of major histocompatibility complex (MHC) class I molecules from the Golgi complex to the endoplasmic reticulum.

Tapasin is a subunit of the transporter associated with antigen processing (TAP). It associates with the major histocompatibility complex (MHC) class I. We show that tapasin interacts with beta- and gamma-subunits of COPI coatomer. COPI retrieves membrane proteins from the Golgi network back to the endoplasmic reticulum (ER). The COPI subunit-associated tapasin also interacts with MHC class I molecules suggesting that tapasin acts as the cargo receptor for packing MHC class I molecules as cargo proteins into COPI-coated vesicles. In tapasin mutant cells, neither TAP nor MHC class I are detected in association with the COPI coatomer. Interestingly, tapasin-associated MHC class I molecules are antigenic peptide-receptive and detected in both the ER and the Golgi. Our data suggest that tapasin is required for the COPI vesicle-mediated retrograde transport of immature MHC class I molecules from the Golgi network to the ER.