Effects of Nitric Oxide on Smooth Muscle Cell Proliferations

一氧化氮对平滑肌细胞增殖的影响

• 批准号: 8035841
• 负责人: Dillip Mohanty
• 金额: $ 40.66万
• 依托单位: CENTRAL MICHIGAN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-01-01 至 2015-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8035841
• 关键词: Address; Alzheimer' s Disease; Amino Acids; Animal Model; Aorta; Arginine; Atherosclerosis; Biochemical; Biochemistry; Biological Assay; Bladder; Blood Pressure; Boronic Acids; Brain; Cardiovascular Diseases; Cause of Death; Cell Culture Techniques; Cell Proliferation; Cell Survival; Cells; Chronic; Citrulline; Clinical Research; Colon; Data; Diagnosis; Disease; Dose; Event; Exhibits; Family; Genital system; Guanosine; Human; Huntington Disease; Hybrids; Immune response; Inflammatory; Intestines; Isoenzymes; Laboratories; Link; Malignant Neoplasms; Measurement; Molecular Weight; Mono-S; N,N-dimethylarginine; Nature; Neurodegenerative Disorders; Neurons; Nitrates; Nitric Oxide; Nitric Oxide Synthase; Organ; Ornithine; Ornithine Decarboxylase; Oxidative Stress; Parkinson Disease; Physiological; Play; Polyamines; Prevention; Principal Investigator; Production; Protocols documentation; Pulmonary artery structure; Putrescine; Regulation; Reporting; Research; Research Personnel; Role; Route; Scourge; Series; Signal Pathway; Smooth Muscle Myocytes; Spermidine; Spermine; Structure; Structure-Activity Relationship; Thymidine; Tissues; Toxic effect; Urea; Water; analytical method; arginase; diazeniumdiolate; enzyme activity; hemodynamics; human disease; in vivo; inhibitor/antagonist; inorganic phosphate; insight; interest; neurotransmission; novel; response; vascular smooth muscle cell proliferation

DESCRIPTION (provided by applicant): A crucial event in the formation of atherosclerotic tissues is excessive proliferation of vascular smooth muscle cells (SMC). Nitrogen monoxide (NO) provided by NO donors has been reported to be beneficial for inhibition of SMC proliferation by reducing polyamine production, activating the NO-cGMP signal pathway and neutralizing oxidative stress. Clinically approved NO donors are nitrate compounds, which are known to induce nitrate tolerance. Experimental and commercially available NO-donors exhibit relatively short half- lives. N-nitroso NO donors recently reported by us release NO in a sustained and controlled fashion with tunable rates. The apparent half-lives of these compounds ranged from 39h to 88h. We have prepared 3 new families of NO donors. The NO release profile of each of the NO-donors can be varied by changing the nature of the moieties attached to the N-nitroso group. Data obtained from cell culture studies with human aortic smooth muscle cells (HASMC), using one of the N-nitroso NO donors (80 pM) exhibited a significant (40%) decrease of SMC proliferation. More importantly, this inhibition was achieved at a very low NO-donor concentration compared to the conventional NO-donors. The proposed studies will address the following issues. First, N-nitroso NO donors (water soluble, water insoluble, low molecular weight, dendritic, pegylated, hybrid, polymeric) will be synthesized and their NO-release profiles will be determined to establish structure- activity relationships. Second, the physiological effect on HASMC of NO released by these novel NO donors will be evaluated by a variety of cell and biochemistry assays including cell viability assay, [3H] thymidine incorporation assay, and determination of arginase, nitric oxide synthase (NOS) and ornithine decarboxylase (ODC) enzyme activities. cGMP and polyamine levels in the cell culture will be determined to evaluate the effect of NO in cultured HASMC. Third, a combination arginase inhibitor, ABH, and N-nitroso NO donors will be used to achieve the "right" physiological NO level in cultured HASMC. Fourth, these combination doses will be used along with elevated level of asymmetric dimethylarginine (ADMA) to determine the beneficial effects of this combination protocol in comparison to those observed with ABH and NO-donor alone. Thus our proposed studies should provide further understanding of the effects of NO released in a slow, sustained and rate-tunable manner from the N-nitroso NO donors on HASMC as well as other SMC, cancer and neuronal cells. PUBLIC HEALTH RELEVANCE: This proposal will involve syntheses of a variety of N-nitroso NO donors and investigate their inhibition of SMC proliferation as well as the influence of structure on NO release profiles. Results of this study will benefit the use of NO donors for the prevention, diagnosis and treatment of human diseases strongly associated with impaired NO production, including cardiovascular disease, neurodegenerative diseases, chronic inflammatory diseases, and cancer.

描述（由申请方提供）：动脉粥样硬化组织形成中的一个关键事件是血管平滑肌细胞（SMC）过度增殖。据报道，由NO供体提供的一氧化氮（NO）通过减少多胺产生、激活NO-cGMP信号通路和中和氧化应激而有益于抑制SMC增殖。临床上批准的NO供体是硝酸盐化合物，已知其诱导硝酸盐耐受性。实验和市售的NO-供体表现出相对短的半衰期。我们最近报道的N-亚硝基NO供体以可调速率以持续和受控的方式释放NO。这些化合物的表观半衰期为39 - 88 h。我们准备了3个新的无供体家庭。每个NO-供体的NO释放曲线可以通过改变连接到N-亚硝基基团的部分的性质来改变。使用一种N-亚硝基NO供体（80 pM），从人主动脉平滑肌细胞（HASMC）的细胞培养研究中获得的数据显示SMC增殖显著降低（40%）。更重要的是，这种抑制是在一个非常低的NO-供体浓度相比，传统的NO-供体。拟议的研究将处理以下问题。首先，将合成N-亚硝基NO供体（水溶性的、水不溶性的、低分子量的、树枝状的、聚乙二醇化的、杂合的、聚合的），并且将测定它们的NO释放曲线以建立结构-活性关系。第二，通过多种细胞和生物化学测定，包括细胞活力测定、[3 H]胸苷掺入测定以及谷胱甘肽转移酶、一氧化氮合酶（NOS）和鸟氨酸脱羧酶（ODC）酶活性的测定，来评价由这些新型NO供体释放的NO对HASMC的生理作用。将测定细胞培养物中的cGMP和多胺水平以评价NO在培养的HASMC中的作用。第三，将使用精氨酸酶抑制剂、ABH和N-亚硝基NO供体的组合来实现培养的HASMC中“正确”的生理NO水平。第四，这些组合剂量将与升高水平的不对称二甲基精氨酸（ADMA）一起沿着使用，以确定该组合方案与单独ABH和NO供体所观察到的那些相比的有益效果。因此，我们提出的研究应提供进一步了解NO释放的影响，在一个缓慢的，持续的和速率可调的方式从N-nitroso NO供体对HASMC以及其他SMC，癌症和神经元细胞。 公共卫生相关性：本研究拟合成多种N-亚硝基NO供体，并研究其对SMC增殖的抑制作用以及结构对NO释放的影响。本研究的结果将有利于NO供体用于预防、诊断和治疗与NO产生受损强烈相关的人类疾病，包括心血管疾病、神经退行性疾病、慢性炎症性疾病和癌症。

项目成果

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.

异构体二胺的二分法作用，该胺含有芳族硝酸和氮基对人主动脉平滑肌细胞的抑制作用。

• DOI: 10.1016/j.biochi.2016.12.010
• 发表时间: 2017-02
• 期刊: Biochimie
• 影响因子: 3.9
• 作者: Ji Y;Bowersock A;Badour AR;Vij N;Juris SJ;Ash DE;Mohanty DK
• 通讯作者: Mohanty DK

Secondary amines containing one aromatic nitro group: preparation, nitrosation, sustained nitric oxide release, and the synergistic effects of released nitric oxide and an arginase inhibitor on vascular smooth muscle cell proliferation.

• DOI: 10.1016/j.bmc.2012.12.043
• 发表时间: 2013-03-01
• 期刊: Bioorganic & medicinal chemistry
• 影响因子: 3.5
• 作者: Curtis B;Payne TJ;Ash DE;Mohanty DK
• 通讯作者: Mohanty DK

Two N-(2-phenylethyl)nitroaniline derivatives as precursors for slow and sustained nitric oxide release agents.

两种 N-(2-苯乙基)硝基苯胺衍生物作为缓慢且持续的一氧化氮释放剂的前体。

• DOI: 10.1107/s2053229616005763
• 发表时间: 2016
• 期刊: Acta crystallographica. Section C, Structural chemistry
• 作者: Badour,AlecR;Wisniewski,JohnA;Mohanty,DillipK;Squattrito,PhilipJ
• 通讯作者: Squattrito,PhilipJ

Models for potential dendritic nitric oxide donors: crystal structures of two 2-nitroanilino precursors and nitric oxide-release behavior of the nitrosated derivatives.

潜在的树枝状一氧化氮供体模型：两种 2-硝基苯胺基前体的晶体结构和亚硝化衍生物的一氧化氮释放行为。

• DOI: 10.1107/s2053229618011737
• 发表时间: 2018
• 期刊: Acta crystallographica. Section C, Structural chemistry
• 作者: Badour,AlecR;Arnett-Butscher,CoreyJ;Mohanty,DillipK;Squattrito,PhilipJ;Lambright,KellyJ;Kirschbaum,Kristin
• 通讯作者: Kirschbaum,Kristin

A series of N-(2-phenylethyl)nitroaniline derivatives as precursors for slow and sustained nitric oxide release agents.

一系列 N-(2-苯乙基)硝基苯胺衍生物，作为缓慢和持续的一氧化氮释放剂的前体。

• DOI: 10.1107/s0108270113025869
• 发表时间: 2013
• 期刊: Acta crystallographica. Section C, Crystal structure communications
• 作者: Wade,ColinB;Mohanty,DillipK;Squattrito,PhilipJ;Amato,NicholasJ;Kirschbaum,Kristin
• 通讯作者: Kirschbaum,Kristin