Anti‐proliferative properties of IPA/NO: a novel use of an HNO‐eluting compound

Abstract

Isopropylamine NONOate (IPA/NO), initially synthesized as a nitric oxide (NO) donor, is now known to be a nitroxyl (HNO) donor at physiological pH. While HNO has been shown to cause vasodilation, little is known about its effect in vascular smooth muscle cells (VSMC). The aim of the current study is to determine the efficacy of IPA/NO as an anti-proliferative agent in VSMC. VSMC were exposed to IPA/NO (100–1000 μM) or the NO donor SNAP (1000 μM) and proliferation was assessed by 3H-thymidine incorporation. IPA/NO induced a concentration-dependent inhibition of VSMC proliferation, similar to SNAP (50% at 24 hrs, 1000 μM). This inhibition was independent of cell death as determined by Guava PCA. To ascertain if the anti-proliferative effects were mediated through the soluble guanylate cyclase (sGC), PI3 kinase, or p38 MAPK pathways, VSMC were exposed to ODQ (20–80 μM), LY292004 (50 μM), and SB202190 (5–20 μM), respectively, prior to addition of IPA/NO. None of these inhibitors prevented IPA/NO-mediated inhibition of VSMC proliferation, indicating that IPA/NO acts independently of these signaling pathways. In conclusion, IPA/NO is a potent inhibitor of VSMC proliferation; however, this inhibition appears to be mediated through a mechanism distinct from NO. These data suggest that IPA/NO may be a good candidate for therapeutic use in the vasculature.