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

Abstract

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.

Multi-omic signatures of atherogenic dyslipidaemia: pre-clinical target identification and validation in humans

“…Interestingly, several papers reported that MNA—a terminal metabolite of nicotinamide clearance—at pharmacological doses, can improve endothelial function in humans and in experimental animals [ 13 , 56 , 57 ]. Domagala et al [ 56 ] demonstrated that MNA ameliorated endothelial dysfunction measured as flow-mediated vasodilation in humans.…”

Alterations in NO- and PGI2- dependent function in aorta in the orthotopic murine model of metastatic 4T1 breast cancer: relationship with pulmonary endothelial dysfunction and systemic inflammation

“…At the stage of advanced metastasis associated with robust systemic inflammation, the NO-dependent response in aorta was impaired, while the endothelium-independent response was preserved. Interestingly, downregulation of a NO-dependent endothelial activity was associated with a compensatory increase in COX-2-mediated synthesis of PGI 2 , a vasoprotective molecule with known anti-metastatic potential [ 11 , 12 , 18 – 20 , 44 ].…”

The effects of renin–angiotensin system inhibitors (RASI) in coronavirus disease (COVID-19) with hypertension: A retrospective, single-center trial

“…Both ACEI and ARB have exact antihypertensive effects, as well as clinical effects such as protecting the cardiovascular and cerebrovascular, improving renal function, reducing left ventricular hypertrophy, preventing heart failure and preventing atrial fibrillation. Existing studies suggest that ACEIs, such as captopril or Lisinopril, do not affect the activity of ACE2, 10 and there is no evidence that ACEI or ARB may bring special effects to patients with COVID-19 infection or new coronary pneumonia damage. So, we recommend that the overall control of patients with new coronary pneumonia is persistent, and most of them do not need to adjust hypertension drugs.…”