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Effects of slow, sustained, and rate-tunable nitric oxide donors on human aortic smooth muscle cells proliferation.

ABSTRACT: Smooth muscle cell (SMC) proliferation has been accepted as a common event in the pathophysiology of vascular diseases, including atherogenesis and intimal hyperplasia. Delivery of the nitric oxide synthase (NOS) substrate l-arginine, pharmacological nitric oxide (NO) donors, NO gas or overexpression of NOS proteins can inhibit SMC proliferation and reduce the injury responses within the blood vessel wall. Although commercial development of NO donors that attempt to provide exogenous delivery of NO has accelerated over the last few years, none of the currently available products can provide controlled, sustained, time-tunable release of NO. Nitrosamine-based NO donors, prepared in our laboratory, present a unique and innovative alternative for possible treatments for long-term NO deficiency-related diseases, including atherosclerosis, asthma, erectile dysfunction, cancer, and neurodegenerative diseases. A family of secondary amines prepared via nucleophilic aromatic displacement reactions could be readily N-nitrosated to produce NO donors. NO release takes place in three distinct phases. During the initial phase, the release rate is extremely fast. In the second phase, the release is slower and the rate remains essentially the same during the final stage. These compounds inhibited up to 35% human aortic smooth muscle cell proliferation in a concentration-dependent manner.

SUBMITTER: Yu H

PROVIDER: S-EPMC3171617 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature

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Effects of slow, sustained, and rate-tunable nitric oxide donors on human aortic smooth muscle cells proliferation.

Yu Hao H Payne Thomas J TJ Mohanty Dillip K DK

Chemical biology & drug design 20110803 4

Smooth muscle cell (SMC) proliferation has been accepted as a common event in the pathophysiology of vascular diseases, including atherogenesis and intimal hyperplasia. Delivery of the nitric oxide synthase (NOS) substrate l-arginine, pharmacological nitric oxide (NO) donors, NO gas or overexpression of NOS proteins can inhibit SMC proliferation and reduce the injury responses within the blood vessel wall. Although commercial development of NO donors that attempt to provide exogenous delivery of ...[more]

PMID: 21740530

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Project description:Notwithstanding its simple structure, the chemistry of nitric oxide (NO) is complex. As a radical, NO is highly reactive. NO also has profound effects on the cardiovascular system. In order to regulate NO levels, direct therapeutic interventions include the development of numerous NO donors. Most of these donors release NO in a single high-concentration burst, which is deleterious. N-Nitrosated secondary amines release NO in a slow, sustained, and rate-tunable manner. Two new precursors to sustained NO-releasing materials have been characterized. N-[2-(3,4-Dimethoxyphenyl)ethyl]-2,4-dinitroaniline, C16H17N3O6, (I), crystallizes with one independent molecule in the asymmetric unit. The adjacent amine and nitro groups form an intramolecular N-H...O hydrogen bond. The anti conformation about the phenylethyl-to-aniline C-N bond leads to the planes of the arene and aniline rings being approximately perpendicular. Molecules are linked into dimers by weak intermolecular N-H...O hydrogen bonds such that each amine H atom participates in a three-center interaction with two nitro O atoms. The dimers pack so that the arene rings of adjacent molecules are not parallel and ?-? interactions do not appear to be favored. N-(4-Methylsulfonyl-2-nitrophenyl)-L-phenylalanine, C16H16N2O6S, (II), with an optically active center, also crystallizes with one unique molecule in the asymmetric unit. The L enantiomer was established via the configuration of the starting material and was confirmed by refinement of the Flack parameter. As in (I), there is an intramolecular N-H...O hydrogen bond between adjacent amine and nitro groups. The conformation of the molecule is such that the arene rings display a dihedral angle of ca 60°. Unlike (I), molecules are not linked via intermolecular N-H...O hydrogen bonds. Rather, the carboxylic acid H atom forms a classic, approximately linear, O-H...O hydrogen bond with a sulfone O atom. Pairs of molecules related by twofold rotation axes are linked into dimers by two such interactions. The packing pattern features a zigzag arrangement of the arene rings without apparent ?-? interactions. These structures are compared with reported analogues, revealing significant differences in molecular conformation, intermolecular interactions, and packing that result from modest changes in functional groups. The structures are discussed in terms of potential NO-release capability.

Project description:2,4-Dinitro-N-(2-phenylethyl)aniline, C14H13N3O4, (I), crystallizes with one independent molecule in the asymmetric unit. The adjacent amine and nitro groups form an intramolecular N-H...O hydrogen bond. The anti conformation about the ethyl C-C bond leads to the phenyl and aniline rings being essentially parallel. Molecules are linked into dimers by intermolecular N-H...O hydrogen bonds, such that each amine H atom participates in a three-centre interaction with two nitro O atoms. Though the dimers pack so that the arene rings of adjacent molecules are parallel, the rings are staggered and π-π interactions do not appear to be favoured. 4,6-Dinitro-N,N'-bis(2-phenylethyl)benzene-1,3-diamine, C22H22N4O4, (II), differs from (I) in the presence of a second 2-phenylethylamine group on the substituted ring. Compound (II) also crystallizes with one unique molecule in the asymmetric unit. Both amine groups are involved in intramolecular N-H...O hydrogen bonds with adjacent nitro groups. Although one ethyl group adopts an anti conformation as in (I), the other is gauche, with the result that the pendant phenyl rings are not parallel. The amine group that is part of the gauche conformation participates in a three-centre N-H...O hydrogen bond with the nitro group of a neighbouring molecule, leading to dimers as in (I). The other amine H atom does not form any intermolecular hydrogen bonds. The packing leads to separations of ca 3.4 Å of the parallel anti phenyl and aminobenzene rings. 2-Cyano-4-nitro-N-(2-phenylethyl)aniline, C15H13N3O2, (III), differs from (I) only in having a cyano group in place of the 2-nitro group. The absence of the adjacent nitro group eliminates the intramolecular N-H...O hydrogen bond. Molecules of (III) adopt the same anti conformation about the ethyl group as in (I), but crystallize in the higher-symmetry monoclinic space group P21/n. The molecules are linked into dimers via N-H...N amine-cyano hydrogen bonds, while the nitro groups are not involved in any N-H...O interactions. Owing to the different symmetry, the molecules pack in a herringbone pattern with fewer face-to-face interactions between the rings. The closest such interactions are about 3.5 Å between rings that are largely slipped past one another. 4-Methylsulfonyl-2-nitro-N-(2-phenylethyl)aniline, C15H16N2O4S, (IV), differs from (I) in having a methylsulfonyl group in place of the 4-nitro group. The intramolecular N-H...O hydrogen bond is present as in (I). However, unlike (I), the conformation about the ethyl group is gauche, so the two arene rings are nearly perpendicular rather than parallel. The packing is significantly different from the other three structures in that there are no intermolecular hydrogen bonds involving the N-H groups. The molecules are arranged in tetragonal columns running along the c axis, with the aniline rings mostly parallel and separated by ca 3.7 Å. Taken together, these structures demonstrate that modest changes in functional groups cause significant differences in molecular conformation, intermolecular interactions and packing.

Project description:Vascular diseases are characterized by the over-proliferation and migration of aortic smooth muscle cells (SMCs), and degradation of extracellular matrix (ECM) within the vessel wall, leading to compromise in cell-cell and cell-matrix signaling pathways. Tissue engineering approaches to regulate SMC over-proliferation and enhance healthy ECM synthesis showed promise, but resulted in low crosslinking efficiency. Here, we report the benefits of exogenous nitric oxide (NO) cues, delivered from S-Nitrosoglutathione (GSNO), to cell proliferation and matrix deposition by adult human aortic SMCs (HA-SMCs) within three-dimensional (3D) biomimetic cocultures. A coculture platform with two adjacent, permeable 3D culture chambers was developed to enable paracrine signaling between vascular cells. HA-SMCs were cultured in these chambers within collagen hydrogels, either alone or in the presence of human aortic endothelial cells (HA-ECs) cocultures, and exogenously supplemented with varying GSNO dosages (0-100?nM) for 21 days. Results showed that EC cocultures stimulated SMC proliferation within GSNO-free cultures. With increasing GSNO concentration, HA-SMC proliferation decreased in the presence or absence of EC cocultures, while HA-EC proliferation increased. GSNO (100?nM) significantly enhanced the protein amounts synthesized by HA-SMCs, in the presence or absence of EC cocultures, while lower dosages (1-10?nM) offered marginal benefits. Multi-fold increases in the synthesis and deposition of elastin, glycosaminoglycans, hyaluronic acid, and lysyl oxidase crosslinking enzyme (LOX) were noted at higher GSNO dosages, and coculturing with ECs significantly furthered these trends. Similar increases in TIMP-1 and MMP-9 levels were noted within cocultures with increasing GSNO dosages. Such increases in matrix synthesis correlated with NO-stimulated increases in endothelial nitric oxide synthase (eNOS) and inducible nitric oxide synthase (iNOS) expression within EC and SMC cultures, respectively. Results attest to the benefits of delivering NO cues to suppress SMC proliferation and promote robust ECM synthesis and deposition by adult human SMCs, with significant applications in tissue engineering, biomaterial scaffold development, and drug delivery.

Dataset Information

Effects of slow, sustained, and rate-tunable nitric oxide donors on human aortic smooth muscle cells proliferation.

Publications

Effects of slow, sustained, and rate-tunable nitric oxide donors on human aortic smooth muscle cells proliferation.

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