NAD+代谢与心血管疾病：机制与治疗策略
人体中的单一分子能否成为心脏健康的关键驱动因素？烟酰胺腺嘌呤二核苷酸（NAD+）正迅速成为科学研究的主要焦点。作为能量代谢的核心参与者，NAD+不仅维持血管弹性和心肌活力，还通过多种机制影响心血管健康，包括调节氧化还原平衡、炎症、自噬和线粒体功能。在心血管疾病（CVD）已成为全球主要死亡原因之一的当下，NAD+的重要性正日益获得科学证据的支持。
图1. NAD+代谢与心血管疾病的治疗策略
NAD+稳态通过多种途径的合成、消耗和再生来维持。这些过程受特定的NAD+消耗酶、生物合成酶和氧化还原反应的调控。
生物体内的NAD+生物合成受三大途径调控： de novo biosynthesis pathway, the Preiss–Handler pathway, and the salvage pathway. The salvage pathway is the primary route, recycling nicotinamide (NAM), a byproduct of NAD+ consumption. In this pathway, nicotinamide phosphoribosyltransferase (NAMPT) converts NAM into nicotinamide mononucleotide (NMN), which is then converted into NAD+ by nicotinamide mononucleotide adenylyltransferase (NMNAT). Metabolically active organs such as the heart rely heavily on this pathway. In the Preiss–Handler pathway, nicotinic acid (NA) is converted into nicotinic acid mononucleotide (NAMN) by nicotinic acid phosphoribosyltransferase (NAPRT), and subsequently into NAD+. The liver and kidneys are the primary organs utilizing this pathway, while its contribution in the heart is relatively limited. In the de novo 合成途径中，色氨酸（Trp）通过犬尿氨酸途径转化为喹啉酸（QA），最终生成NAD+。该途径对心脏中NAD+的产生贡献甚微。
NAD+的消耗通过氧化还原反应和NAD+依赖性酶发生：
图2. NAD+代谢途径
图3. NAD+与血管健康的关系
心脏是人体代谢最活跃的器官之一，线粒体功能障碍是心力衰竭的标志。NAD+缺乏通过以下机制加剧氧化应激，导致内皮氧化损伤并促进动脉粥样硬化斑块形成：
CD38介导的NAD+耗竭: During aging or metabolic disorders, CD38 is highly expressed in macrophages and endothelial cells, promoting the release of pro-inflammatory cytokines (such as IL-6 and TNF-α) while suppressing the anti-inflammatory effects of SIRT1.
SIRT1和SIRT6的抗炎途径: SIRT1 suppresses inflammatory signaling by deacetylating NF-κB, while SIRT6 regulates glucose metabolism and genomic stability. Dysfunction of these pathways accelerates vascular disease progression.
SIRT1–FOXO pathway：NAD+激活SIRT1以促进自噬相关基因（如Atg7）的表达，从而维持内皮细胞稳态。
NAM诱导的自噬抑制：过量的NAM抑制SIRT1，增加Atg7乙酰化，并阻断自噬体形成。
Rajah 4. Terapi suplemen NAD+ dan kesannya terhadap CVD
图1. NAD+代谢与心血管疾病的治疗策略
一、NAD+代谢途径
NAD+稳态通过多种途径的合成、消耗和再生来维持。这些过程受特定的NAD+消耗酶、生物合成酶和氧化还原反应的调控。
生物体内的NAD+生物合成受三大途径调控： de novo biosynthesis pathway, the Preiss–Handler pathway, and the salvage pathway. The salvage pathway is the primary route, recycling nicotinamide (NAM), a byproduct of NAD+ consumption. In this pathway, nicotinamide phosphoribosyltransferase (NAMPT) converts NAM into nicotinamide mononucleotide (NMN), which is then converted into NAD+ by nicotinamide mononucleotide adenylyltransferase (NMNAT). Metabolically active organs such as the heart rely heavily on this pathway. In the Preiss–Handler pathway, nicotinic acid (NA) is converted into nicotinic acid mononucleotide (NAMN) by nicotinic acid phosphoribosyltransferase (NAPRT), and subsequently into NAD+. The liver and kidneys are the primary organs utilizing this pathway, while its contribution in the heart is relatively limited. In the de novo 合成途径中，色氨酸（Trp）通过犬尿氨酸途径转化为喹啉酸（QA），最终生成NAD+。该途径对心脏中NAD+的产生贡献甚微。
NAD+的消耗通过氧化还原反应和NAD+依赖性酶发生：
在氧化还原反应中，NAD+在糖酵解和线粒体呼吸过程中被还原为NADH。NAD+/NADH氧化还原比直接影响代谢途径的活性。
NAD+ serves as a co-substrate for various enzymes, including poly(ADP-ribose) polymerases (PARPs), sirtuins, CD38/CD157, and SARM1. These enzymes use NAD+ to regulate diverse biological processes. The sirtuin family (SIRT1–7) is involved in deacetylation and regulates mitochondrial function, stress responses, and aging. PARPs consume large amounts of NAD+ during DNA repair, and their overactivation can lead to NAD+ depletion. CD38/CD157 hydrolyze NAD+ to produce cyclic ADP-ribose (cADPR) and nicotinic acid adenine dinucleotide phosphate (NAADP); their overexpression is associated with aging and inflammation.
图2. NAD+代谢途径
二、NAD+缺乏与心血管疾病关联的机制
NAD+在维持血管健康中发挥多重作用。一方面，NAD+水平降低会损害线粒体功能和自噬，导致受损线粒体、凋亡细胞和受损DNA的积累。另一方面，NAD+缺乏会增强炎症反应、氧化应激和蛋白质乙酰化，从而减少血流量并抑制内皮细胞迁移和脂质稳态。这些因素共同进一步加剧了心血管疾病（CVD）的患病率。
图3. NAD+与血管健康的关系
1. 氧化应激与线粒体功能障碍
心脏是人体代谢最活跃的器官之一，线粒体功能障碍是心力衰竭的标志。NAD+缺乏通过以下机制加剧氧化应激，导致内皮氧化损伤并促进动脉粥样硬化斑块形成：
抑制SIRT3活性：SIRT3是线粒体蛋白（如SOD2和IDH2）的NAD+依赖性去乙酰化酶。SIRT3活性降低会减弱活性氧（ROS）清除能力。
NAD+/NADH比例失衡: Under chronic stress or ischemia–reperfusion injury, impaired mitochondrial complex I function leads to NADH accumulation, inhibiting fatty acid oxidation and pyruvate dehydrogenase activity, thereby worsening the energy crisis.
2. 炎症反应
慢性低度炎症是动脉粥样硬化、高血压及相关疾病的病理基础。NAD+通过以下机制调节炎症：CD38介导的NAD+耗竭: During aging or metabolic disorders, CD38 is highly expressed in macrophages and endothelial cells, promoting the release of pro-inflammatory cytokines (such as IL-6 and TNF-α) while suppressing the anti-inflammatory effects of SIRT1.
SIRT1和SIRT6的抗炎途径: SIRT1 suppresses inflammatory signaling by deacetylating NF-κB, while SIRT6 regulates glucose metabolism and genomic stability. Dysfunction of these pathways accelerates vascular disease progression.
3. 自噬受损
自噬对于清除受损细胞器和蛋白质至关重要，其功能障碍与心肌肥大和血管硬化密切相关：SIRT1–FOXO pathway：NAD+激活SIRT1以促进自噬相关基因（如Atg7）的表达，从而维持内皮细胞稳态。
NAM诱导的自噬抑制：过量的NAM抑制SIRT1，增加Atg7乙酰化，并阻断自噬体形成。
4. PARP和CD38的过度激活
In ischemia–reperfusion injury or diabetic cardiomyopathy, DNA damage and oxidative stress lead to excessive PARP1 activation, consuming large amounts of NAD+. This suppresses glycolysis and mitochondrial respiration and accelerates cell death. Overexpression of CD38 further aggravates NAD+ depletion, creating a vicious cycle.III. Strategi Terapeutik untuk Suplemen NAD+
Beberapa strategi boleh meningkatkan tahap NAD+, termasuk suplemen dengan prekursor NAD+ dan perencatan enzim yang menggunakan NAD+. Kajian mencadangkan bahawa strategi gabungan mungkin menghasilkan hasil kardiovaskular yang lebih baik. Dalam aterosklerosis, tahap NAD+ yang tinggi mengurangkan keradangan kronik dan menurunkan kolesterol LDL. NAD+ juga meningkatkan fungsi endotelium dan vasodilatasi. Dalam penyakit arteri koronari, peningkatan tahap NAD+ memperbaiki autophagy dan fungsi mitokondria sambil mengurangkan penghasilan ROS, keradangan, dan nekrosis tisu.
Rajah 4. Terapi suplemen NAD+ dan kesannya terhadap CVD
1. Suplemen dengan Prekursor NAD+
NAD+ precursors directly or indirectly participate in NAD+ biosynthesis through different metabolic pathways and represent the most extensively studied intervention strategy. Dietary supplementation with NAD+ precursors—such as tryptophan, NA, NAM, nicotinamide riboside (NR), and NMN—effectively increases NAD+ levels in both animals and humans.2. Perencatan Enzim yang Menggunakan NAD+
Menghalang pengaktifan berlebihan enzim yang menggunakan NAD+ mengurangkan kekurangan NAD+ yang tidak perlu dan amat bermanfaat dalam penyakit yang berkaitan dengan tekanan oksidatif atau kerosakan DNA.
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| Suplemen NAD+ | Tempoh | Peserta | Saiz Sampel | Hasil | ID Ujian |
| NMN | 60 hari | Healthy adults aged 40–65 | 66 | Perubahan dalam tahap NAD+/NADH serum dan tekanan darah | NCT04228640 |
| NMN | 28 hari | Healthy volunteers aged 30–60 | 20 | Perubahan dalam tekanan darah arteri, kadar denyutan jantung, dan lipid darah | NCT04862338 |
| NR | 6 minggu | Dewasa pertengahan umur yang sihat | 30 | Perubahan tekanan darah | NCT02921659 |
| NR | 6 minggu | Pesakit tua dengan hipertensi | 49 | Perubahan dalam tekanan darah sistolik dan kekakuan arteri | NCT04112043 |
| NR | 3 bulan | Pesakit dengan penyakit buah pinggang kronik sederhana hingga teruk | 118 | Perubahan dalam kekakuan aorta dan tekanan darah arteri | NCT04040959 |
| NAM | 48 bulan | Wanita dengan preeklampsia onset awal | 25 | Perubahan dalam tekanan darah min | NCT03419364 |
