Research Group

  • Dr. Michael Autieri, Principal Investigator
  • Christopher Carbone, Research Associate

Location

  • Temple University, Philadelphia, USA

Title

  • Characterization of Expression and Growth-Enhancing Properties of AIF-1 in VSMC of Injured Arteries

The initiation of allograft vasculopathy (AV) is believed to involve a chronic immune response of the recipient to the donor vasculature in which activated recipient immune cells produce cytokines that activate medial vascular smooth muscle cells (VSMC). The activation of VSMC is responsible for most of the obliterative arterial intimal thickening and is the major complication that limits long-term survival of transplanted solid organs. Interventions that are successful in patients with conventional coronary artery disease are not applicable to the majority of patients with AV because of its extensive nature. The risk of infection and malignancy associated with aggressive immunosuppressive therapy also advocates the need to identify a molecular target that directly impacts the VSMC response to injury.

We feel that allograft inflammatory factor-1 (AIF-1) is one of several calcium-binding proteins that play a critical role in the regulation of cellular growth. AIF-1 is not expressed in normal arteries, or in arteries from failing human hearts, but is rapidly expressed in VSMC in response to balloon angioplasty or allograft injury. AIF-1 expression correlates with proliferation of VSMC during in vivo injury and in cultured VSMC. Correspondingly, stable transfection and constitutive expression of AIF-1 in human VSMC leads to enhanced proliferation and increased expression of proliferative genes in those cells. Conversely, inhibition of AIF-1 expression or modification of AIF-1 calcium binding greatly reduces the proliferative capacity of VSMC.

The specific aims of this project are to define the mechanism of AIF-1 growth-enhancing activity in human VSMC, characterize the expression pattern of AIF-1 and its sensitivity to various therapeutic compounds, and explore the use of AIF-1 as a surrogate marker of VSMC pathophysiology. We anticipate that inhibition of AIF-1 expression and/or activity will reduce or prevent VSMC proliferation, thereby limiting the severity of transplant restenosis and other vascular proliferative diseases.