Functional and Biochemical Endothelial Profiling In Vivo in a Murine Model of Endothelial Dysfunction; Comparison of Effects of 1-Methylnicotinamide and Angiotensin-converting Enzyme Inhibitor.
Functional and Biochemical Endothelial Profiling In Vivo in a Murine Model of Endothelial Dysfunction; Comparison of Effects of 1-Methylnicotinamide and Angiotensin-converting Enzyme Inhibitor.
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DOI：
10.3389/fphar.2017.00183
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发表时间：
2017
影响因子：
5.6
通讯作者：
Chlopicki S
中科院分区：
文献类型：
--
作者：
Bar A;Olkowicz M;Tyrankiewicz U;Kus E;Jasinski K;Smolenski RT;Skorka T;Chlopicki S
尽管已知1 - 甲基烟酰胺（MNA）在小鼠中显示出血管保护活性，但MNA对内皮功能的影响尚未在体内得到证实。在此，我们利用磁共振成像（MRI）在体内对动脉粥样硬化小鼠（ApoE/LDLR - / -）中MNA对内皮表型的影响进行了分析，并与具有已知血管保护活性的血管紧张素（Ang） - 转换酶（ACE）抑制剂（培哚普利）进行了比较。在生化水平上，我们分析了MNA或培哚普利诱导的内皮功能改善是否导致ACE/Ang II - ACE2/Ang -（1 - 7）平衡以及L - 精氨酸/不对称二甲基精氨酸（ADMA）比值的变化。在4个月大的未治疗或分别用MNA（100 mg/kg/天）或培哚普利（10 mg/kg/天）治疗1个月或2个月的ApoE/LDLR - / -小鼠的头臂动脉（BCA）中评估内皮功能和通透性。使用3D IntraGate®FLASH序列评估乙酰胆碱（Ach）给药后BCA体积的变化，并在BCA周围进行弛豫时间（T1）映射，使用血管内造影剂评估内皮通透性。使用基于液相色谱/质谱的方法测量ACE/Ang II和ACE2/Ang -（1 - 7）通路的活性以及L - 精氨酸/ADMA通路的代谢产物。在未治疗的6个月大的ApoE/LDLR - / -小鼠中，Ach诱导BCA血管收缩达 - 7.2%。用MNA或培哚普利治疗2个月导致受损的Ach诱导的血管舒张反应逆转（分别为4.5%和5.5%），并且内皮通透性降低（MNA以及培哚普利治疗的小鼠均降低约60%）。在这两种情况下，MNA和培哚普利对内皮功能的改善都与ACE2/Ang -（1 - 7）的激活以及ACE/Ang II轴的抑制有关，这表现为Ang -（1 - 9）和Ang -（1 - 7）大约增加两倍，Ang II及其活性代谢产物成比例减少。最后，与未治疗的小鼠相比，MNA和培哚普利治疗导致L - 精氨酸/ADMA比值分别增加107%（MNA）和140%（培哚普利）。对ApoE/LDLR - / -小鼠在体内进行的内皮功能和生化分析表明，用MNA（100 mg/kg/天）治疗2个月显示出与用培哚普利（10 mg/kg/天）治疗2个月相似的血管保护作用特征：即内皮功能的改善与血浆中ACE/Ang II - ACE2/Ang（1 - 7）平衡以及L - 精氨酸/ADMA比值的有益变化有关。
Although it is known that 1-methylnicotinamide (MNA) displays vasoprotective activity in mice, as yet the effect of MNA on endothelial function has not been demonstrated in vivo. Here, using magnetic resonance imaging (MRI) we profile the effects of MNA on endothelial phenotype in mice with atherosclerosis (ApoE/LDLR-/-) in vivo, in comparison to angiotensin (Ang) -converting enzyme (ACE) inhibitor (perindopril), with known vasoprotective activity. On a biochemical level, we analyzed whether MNA- or perindopril-induced improvement in endothelial function results in changes in ACE/Ang II-ACE2/Ang-(1–7) balance, and L-arginine/asymmetric dimethylarginine (ADMA) ratio. Endothelial function and permeability were evaluated in the brachiocephalic artery (BCA) in 4-month-old ApoE/LDLR-/- mice that were non-treated or treated for 1 month or 2 months with either MNA (100 mg/kg/day) or perindopril (10 mg/kg/day). The 3D IntraGate®FLASH sequence was used for evaluation of BCA volume changes following acetylcholine (Ach) administration, and for relaxation time (T1) mapping around BCA to assess endothelial permeability using an intravascular contrast agent. Activity of ACE/Ang II and ACE2/Ang-(1–7) pathways as well as metabolites of L-arginine/ADMA pathway were measured using liquid chromatography/mass spectrometry-based methods. In non-treated 6-month-old ApoE/LDLR-/- mice, Ach induced a vasoconstriction in BCA that amounted to –7.2%. 2-month treatment with either MNA or perindopril resulted in the reversal of impaired Ach-induced response to vasodilatation (4.5 and 5.5%, respectively) and a decrease in endothelial permeability (by about 60% for MNA-, as well as perindopril-treated mice). Improvement of endothelial function by MNA and perindopril was in both cases associated with the activation of ACE2/Ang-(1–7) and the inhibition of ACE/Ang II axes as evidenced by an approximately twofold increase in Ang-(1–9) and Ang-(1–7) and a proportional decrease in Ang II and its active metabolites. Finally, MNA and perindopril treatment resulted in an increase in L-arginine/ADMA ratio by 107% (MNA) and 140% (perindopril), as compared to non-treated mice. Functional and biochemical endothelial profiling in ApoE/LDLR-/- mice in vivo revealed that 2-month treatment with MNA (100 mg/kg/day) displayed a similar profile of vasoprotective effect as 2-month treatment with perindopril (10 mg/kg/day): i.e., the improvement in endothelial function that was associated with the beneficial changes in ACE/Ang II-ACE2/Ang (1–7) balance and in L-arginine/ADMA ratio in plasma.