Role of vascular smooth muscle Bcl11b in arterial stiffness

烟酰胺腺嘌呤二核苷酸(NAD)是相关酶活性的重要辅助因子 在细胞代谢动态平衡、氧化还原平衡、DNA合成和应激反应中。NAD是 从色氨酸合成的从头开始，但它的功能是如此基本的细胞功能，哺乳动物 进化出一条抢救途径，利用各种底物持续补充细胞内的NAD。 在NAD前体中，烟酰胺(NAM)、烟酰胺单核苷酸(NMN)和烟酰胺 核糖苷(NR)是商业上可用的膳食补充剂；然而，我们并不完全了解 它们的全部生物学效应，特别是对心血管系统的影响，这将是 本研究建议的重点。临床上重要的是，NAD水平已经显示出显著的 随着肥胖和衰老而减少，这是心血管疾病(CVD)的最高风险因素。 我们推测，通过膳食补充剂补充细胞内NAD是一种可行的方法 减轻心血管疾病，心血管疾病仍然是日益肥胖的人发病和死亡的主要原因 和老龄化的美国人口。最近的证据表明，给予NAM和NMN 实验动物显著增加心脏和脂肪中的NAD水平，预防糖尿病和 肥胖小鼠/大鼠的糖尿病心力衰竭。此外，NMN已被证明可以防止动脉硬化。 以及老年小鼠的高血压。然而，无论日粮中添加NMN还是NR都会增加 血管系统中的NAD水平以及这些水平的增加是否导致与 潜在有益的血管效应还没有完全被了解。这项补充提案的目标是 是为了调查膳食中补充NMN、NR或这两种补充剂的组合 给小鼠增加血管系统中的NAD水平(目标1)。我们还将确定这是否 补充剂可以保护血管功能，测量动脉顺应性和血压， 在肥胖和衰老小鼠中，通过增加血管细胞中NAD水平和激活下游抗 炎症和抗氧化途径(目标2)。成功完成这些临床前、经证明的 概念研究将填补关于NAD前体血管效应的知识空白，并将指导 合理使用NAD前体(NMN、NR)作为膳食补充剂。

Nicotinamide adenine dinucleotide (NAD+) is an essential co-factor for the activity of enzymes involved in cellular metabolic homeostasis, redox balance, DNA synthesis, and stress response. NAD+ is synthetized de novo from tryptophan, but its function is so fundamental to cellular function that mammals evolved a salvage pathway to continuously replenish intracellular NAD+ using a variety of substrates. Among NAD+ precursors, nicotinamide (NAM), nicotinamide mononucleotide (NMN), and nicotinamide riboside (NR) are commercially available as dietary supplements; however, we do not fully understand the full spectrum of their biological effects, specifically on the cardiovascular system, which will be the focus of this research proposal. Of clinical importance, NAD+ levels have been shown to drastically decrease with obesity and aging, which are the highest risk factors for cardiovascular disease (CVD). We postulate that replenishing intracellular NAD+ via dietary supplements is a viable approach to attenuating CVD, which remain the primary cause of morbidity and mortality in an increasingly obese and aging American population. Recent evidence indicate that administering NAM and NMN to experimental animals significantly increases NAD+ levels in heart and fat, preventing diabetes and diabetic heart failure in obese mice/rats. Moreover, NMN has been shown to prevent arterial stiffening and hypertension in aged mice. However, whether dietary supplementation of NMN or NR increases NAD+ levels in the vasculature and whether these increased levels lead to molecular mechanisms with potentially beneficial vascular effects are not fully understood. The goal of this supplemental proposal is to investigate whether dietary supplementation of NMN, NR, or a combination of the two supplements to mice increases NAD+ levels in the vasculature (Aim 1). We will also determine whether this supplementation can preserve vascular function, measured as arterial compliance and blood pressure, in obese and aged mice, by increasing NAD+ levels in vascular cells and activating downstream anti- inflammatory and anti-oxidant pathways (Aim 2). Successful completion of these preclinical, proof-of- concept studies will fill a gap in knowledge on the vascular effects of NAD+ precursors and will guide rational use of NAD+ precursors (NMN, NR) as dietary supplements.