title: Dichotomous effects of isomeric secondary amines containing an aromatic nitrile and nitro group on human aortic smooth muscle cells via inhibition of cystathionine-γ-lyase.
abstract: Excessive proliferation of vascular smooth muscle cells (SMC) is an important contributor to the progression of atherosclerosis. Inhibition of proliferation can be achieved by endogenously produced and exogenously supplied nitrogen monoxide, commonly known as nitric oxide (NO). We report herein the dichotomous effects of two isomeric families of secondary amines, precursors to the N-nitrosated NO-donors, on HASMC proliferation. The syntheses of these two families were carried out using two equivalents of homologous, aliphatic monoamines and 2,6-difluoro-3-nitrobenzonitrile (2,6-DFNBN, O family) or 2,4-difluoro-5-nitrobenzonitrile (2,4-DFNBN, P family). The secondary amines belonging to the P family inhibited HASMC proliferation at all concentrations, whereas the O family induced HASMC proliferation at low concentrations, and exhibited inhibitory properties at high concentrations. A probable explanation of these behaviors is proposed herein. l-homocysteine (HCY) is known to induce HASMC proliferation at low concentrations (<1 mM) and inhibit HASMC proliferation at higher concentrations (>2.5 mM). Our findings suggest that these two families of amines inhibit cystathionine-γ-lyase (CSE) to varying extents, which directly results in altered levels of intracellular HCY and consequent changes in HASMC proliferation.
authors.affiliation: College of Osteopathic Medicine, Michigan State University, East Lansing, MI 48824, USA.
authors.forename: Yajing
authors.initials: Y
authors.lastname: Ji
authors.affiliation: Department of Chemistry and Biochemistry, Central Michigan University, Mount Pleasant, MI 48859, USA.
authors.forename: Austin
authors.initials: A
authors.lastname: Bowersock
authors.affiliation: Department of Chemistry and Biochemistry, Central Michigan University, Mount Pleasant, MI 48859, USA.
authors.forename: Alec R
authors.initials: AR
authors.lastname: Badour
authors.affiliation: College of Medicine, Central Michigan University, Mount Pleasant, MI 48859, USA.
authors.forename: Neeraj
authors.initials: N
authors.lastname: Vij
authors.affiliation: Department of Biology, Central Michigan University, Mount Pleasant, MI 48859, USA.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Juris
authors.affiliation: Department of Chemistry and Biochemistry, Central Michigan University, Mount Pleasant, MI 48859, USA.
authors.forename: David E
authors.initials: DE
authors.lastname: Ash
authors.affiliation: Department of Chemistry and Biochemistry, Central Michigan University, Mount Pleasant, MI 48859, USA. Electronic address: Mohan1dk@cmich.edu.
authors.forename: Dillip K
authors.initials: DK
authors.lastname: Mohanty
mesh_terms: D000588:Amines / Q000008:administration & dosage / Q000737:chemistry*; D001011:Aorta / Q000166:cytology / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects*; D003542:Cystathionine gamma-Lyase / Q000037:antagonists & inhibitors*; D006801:Humans; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000201:enzymology; D009569:Nitric Oxide / Q000096:biosynthesis* / Q000737:chemistry; D020030:Nitric Oxide Donors / Q000737:chemistry; D009570:Nitriles / Q000737:chemistry
chemical_list: D000588:Amines; D020030:Nitric Oxide Donors; D009570:Nitriles; D009569:Nitric Oxide; D003542:Cystathionine gamma-Lyase
keywords: Cystathionine-γ-lyase; Human aortic smooth muscle cell proliferation inducers and inhibitors; Isomeric secondary amines; l-homocysteine