Antisense to transforming growth factor-β1 messenger RNA reduces vein graft intimal hyperplasia and monocyte chemotactic protein 1

Abstract

The main cause of occlusion and graft failure after peripheral and cardiac arterial reconstruction is IH. The study of the mechanisms and mediators of IH, including TGF-beta1, should lead to future gene therapies to prevent or limit IH. The clinical effect of such treatments would be enormous, because they would increase graft longevity, thereby enhancing quality of life and enabling patients to live without the threat of limb loss or recurrent heart attack.

SM16, an Orally Active TGF-β Type I Receptor Inhibitor Prevents Myofibroblast Induction and Vascular Fibrosis in the Rat Carotid Injury Model

“…The ability of SM16 to prevent adventitial myofibroblast induction, collagen production, and neointimal thickening without significant effect on proliferation is similar to that seen with the soluble TGF-␤RII:Fc. 5,7 These results and those obtained with anti-TGF-␤1 ribozymes 15,16 and anti-TGF-␤1 antibodies 13 highlight the key role played by TGF-␤ in vascular fibrosis. SM16 treatment has a significant effect on the early adventitial myofibroblast induction response to balloon catheter injury.…”

“…The subsequent interaction of this complex with their respective type I receptors, ALK5 and ALK4, allows the interaction with and phosphorylation of type I receptor-associated signaling proteins, Smad2 and Smad3. 11,12 Blockade of TGF-␤ signaling with either the soluble TGF-␤ type II receptor extracellular domain-Fc fusion protein (sTGF-␤RII:Fc), 5,7 antibodies to TGF-␤1, 13 decorin, 14 TGF-␤ antisense oligonucleotides, [15][16][17] or adenovirus Smad7 18 was shown previously to inhibit vascular fibrosis in animal models. Here, we identified SM16, a potent, selective and orally active ALK5/ALK4 kinase inhibitor which potently inhibits TGF-␤-induced phosphorylation of Smad2 and Smad3 in cells and neointimal thickening and vascular remodeling in the rat carotid balloon injury model.…”

Adenovirus-mediated gene transfer of fibromodulin inhibits neointimal hyperplasia in an organ culture model of human saphenous vein graft disease

“…Further studies to clarify these mechanisms are warranted. Inhibition of TGF-b1 is frequently associated with reduced vessel collagen content in vascular injury 11,30,31 (although not invariably 9 ) and reduced collagen content is typically associated with reduced NIH 30,31 (although once again, not invariably 32 ). It is possible therefore that the effects of fibromodulin and decorin are mediated entirely by antagonism of TGF-b1.…”

“…10,11 Two small leucinerich proteoglycans (SLRPs), fibromodulin and decorin, possess TGF-b1 and TGF-b3 antagonist activity in vitro and in vivo. [12][13][14][15] Studies of decorin gene transfer into injured arteries have demonstrated significant inhibition of NIH.…”

Antisense to Transforming Growth Factor-β₁ Facilitates the Apoptosis of Macrophages in Rat Vein Grafts

“…TGF-β 1 protein is found in two forms, an inactivated form associated with the TGF-β 1 latency protein and an active form cleaved from the latency protein. In the natural course of maturation of the grafted vein, both these forms peak at 4 weeks after surgery [21]. In our previous work, we showed that adenovirus-mediated antisense to TGF-β 1 RNA treatment was able to knock down TGF-β 1 mRNA production and protein levels in rat femoral artery vein grafts and reduce IH formation [21].…”