Invited commentary

Abstract

The purpose of this experimental animal study was to test the hypothesis that a 14-day course of intravenous human urinary kininogenase (HUK, 0.02 paranitroaniline unit) would attenuate balloon-injured carotid neointimal formation in New Zealand White rabbits fed a high-fat diet. The results were strongly positive: treatment with intravenous HUK inhibited the formation of arterial neointima by >50%, with accompanying reductions in macrophage infiltration, tumor necrosis factor-α, interleukin-1β, and transforming growth factor-β1 message and expression of transforming growth factor-β1 and p-Smad2/3 protein. So convinced were the investigators that they even demonstrated the effect angiographically after 2 months, a rarity for animal studies of this kind. The search for a safe and effective systemic method for the inhibition of neointimal proliferation after vascular or endovascular intervention has been both arduous and futile. Although significant strides have been made in controlling thrombotic and access complications, and drug-eluting stents and balloons inhibit restenosis on a local level, no systemic pharmacologic therapy has yet been shown to safely and effectively attenuate vascular proliferation. Many classes of agents have been tested, including lipid lowering drugs, antihypertensives, antiproliferatives, antiflammatories, antithrombotics, and antioxidants, but to date, none have consistently proven useful in the clinical arena. HUK represents a potentially new agent for the prevention of restenosis after vascular intervention. Made from fresh human urine, it is a tissue kallikrein with profound effects on multiple cellular processes such as inflammation, cytokine release, cellular proliferation, and membrane stabilization. Intravenous treatment with HUK has been found to reduce neurologic impairment and improve long-term outcomes after stroke; in fact, it has recently been approved in China for this indication using a dose similar to that used in this experimental study. Hopefully, the clinical safety profile of HUK will ultimately prove mild enough to also be considered for the postprocedural prevention of arterial restenosis. Human urine kininogenase attenuates balloon-induced intimal hyperplasia in rabbit carotid artery through transforming growth factor β1/Smad2/3 signaling pathwayJournal of Vascular SurgeryVol. 64Issue 4PreviewEffective treatments against restenosis after percutaneous transluminal angioplasty and stenting are largely lacking. Human tissue kallikrein gene transfer has been shown to be able to attenuate neointima formation induced by balloon catheter. As a tissue kallikrein in vivo, human urinary kininogenase (HUK) is widely used to prevent ischemia-reperfusion injury. However, the effects of HUK on neointima formation have not been explored. We therefore investigated whether HUK could alleviate balloon catheter-induced intimal hyperplasia in rabbits fed with high-fat diets. Full-Text PDF Open Archive