According to the latest statistics from the American Heart Association in 2020, cardiovascular diseases (CVD) remain the leading cause of death globally, imposing significant economic burdens. Adipose tissue has gradually drawn scholars' attention as an important factor influencing the occurrence and development of CVD. Visfatin is a novel adipokine secreted by adipose tissue, known for its function in inducing B cell maturation and nicotinamide phosphoribosyltransferase activity. It is also referred to as pre-B-cell colony-enhancing factor (PBEF) and nicotinamide phosphoribosyltransferase (NAMPT). Visfatin/NAMPT/PBEF are actually different expressions of the same protein in different tissues, and their diverse names reflect their functional diversity. In mammals, visfatin exists in two isoforms: intracellular nicotinamide phosphoribosyltransferase (iNAMPT) and extracellular nicotinamide phosphoribosyltransferase (eNAMPT). iNAMPT plays a central role in enzymatic activity dependent on nicotinamide adenine dinucleotide, while eNAMPT can be synthesized by many cells, mediating interactions between organs.
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A large body of research has confirmed the potential cardiovascular effects of visfatin, involving various pathophysiological processes of CVD. Its broad impact is reflected in its potential involvement in various diseases, including atherosclerosis, acute myocardial infarction, atrial fibrillation, hypertension, and others, through its participation in processes such as glucose and lipid metabolism, oxidative stress, inflammation, and endothelial dysfunction.
Structure of Visfatin
The gene encoding visfatin was first isolated from a human peripheral blood lymphocyte cDNA library. It is located between the chromosomal segments 7q22.1 and 7q31.33, composed of 11 exons and 10 introns. All exon/intron splice sites conform to the GT-AG rule, with a total length of approximately 34.7 kb and a molecular weight of 52 kDa. The crystal structure of visfatin/NAMPT belongs to the dimeric class of type II phosphoribosyltransferases, consisting of two monomers containing 491 residues each. Each monomer is arranged into two structural domains with 19 β-turns and 13 α-helices. The first domain is composed of seven anti-parallel β-strands (β1, β3, β5, β14, β15, β18, and β19), two anti-parallel β-turns (β2 and β4; β16 and β17), and one α-helix bundle (part of α1, α2, α3, α4, α13, and α5), while the second domain consists of β-turns β6-β12 and α-helices α5-α12 forming a classical (β/α)8-barrel.
Fig. 1 Crystal structure of visfatin (Dakroub A., et al. 2021).
Secretion and Expression of Visfatin
Currently, visfatin is believed to be mainly secreted by three types of cells: adipocytes, macrophages, and skeletal muscle cells. Interestingly, studies have found that it is primarily secreted by macrophages rather than adipocytes. At the cellular level, visfatin is secreted into the extracellular space via an unclear mechanism and has been identified in both the nucleus and cytoplasm. Its role as an enzyme activity of NAMPT is exerted within the latter. Visfatin is expressed in various organs of the human body, with the highest levels found in bone marrow, muscles, and liver. Following are the brain, kidneys, testes, and lungs, while the expression in visceral fat is often higher than in subcutaneous fat. Additionally, during pregnancy, visfatin can also be released through the placenta.
Visfatin and CVD
Visfatin and Atherosclerosis
Atherosclerosis is the most common cause of CVD, where vascular inflammation plays a crucial role in its formation. This process involves the recruitment of immune cells to the intima of arteries, foam cell formation, and the release of inflammatory mediators, promoting further recruitment of immune cells and cell proliferation, ultimately leading to complex lesions or plaque formation. Several studies have indicated a certain association between high levels of visfatin and atherosclerotic inflammation and plaque formation. Nuclear factor-κB (NF-κB), known as a key regulator of processes such as cell adhesion, migration, invasion, metastasis, and angiogenesis, is involved. Visfatin can induce endothelial dysfunction through the NF-κB pathway in endothelial cells, activating matrix metalloproteinases, and stimulating phosphoinositide 3-kinase, thereby exerting proliferative, pro-inflammatory, and angiogenic effects. Researchers have found that visfatin can induce endothelial dysfunction through Toll-like receptor 4 (TLR4) mediation. These are all key factors in promoting the progression of atherosclerosis and plaque instability. Although some studies have reported the promoting effect of visfatin on atherosclerosis and plaque, other studies have also found that visfatin can promote collagen synthesis by promoting smooth muscle cell proliferation and activating endothelial nitric oxide synthase to improve endothelial cell function. At the same time, high levels of visfatin can secrete anti-inflammatory factors such as IL-10 and IL-1Ra to alleviate inflammation. It is worth noting that these effects can delay the progression of atherosclerosis and reduce the risk of plaque rupture. Therefore, further research is needed to elucidate the biological effects and exact mechanisms of visfatin in atherosclerosis.
Visfatin and Acute Myocardial Infarction (AMI)
AMI is an acute event of coronary artery atherosclerotic heart disease, characterized by acute myocardial ischemia due to coronary artery blockage, leading to localized myocardial cell necrosis. The inflammation during AMI is a highly complex multi-stage reaction involving the secretion of numerous cytokines and chemokines. Some literature categorizes visfatin as one of the pro-inflammatory adipokines involved in AMI. Researchers found abundant visfatin in foam cells of unstable plaques in AMI patients and in vitro experiments, suggesting its potential role in promoting atherosclerosis and plaque inflammation. Research has found that visfatin levels increase upon admission in patients with acute ST-segment elevation myocardial infarction (STEMI), peaking at 24 hours post-percutaneous coronary intervention (PCI) and declining after one week, positively correlating with myocardial enzymes. Furthermore, compared to patients with low plasma visfatin levels, those with high levels have increased mortality rates and rates of recurrent target lesion revascularization.
Visfatin may influence ventricular remodeling post-myocardial infarction through various mechanisms. In an animal model, visfatin activation of phosphatidylinositol 3-kinase (PI3K)/AKT/HSP70 signaling pathway promotes HSP70 expression, reducing myocardial cell inflammation and apoptosis levels, thus protecting the myocardium from ischemia-reperfusion injury.
Visfatin acts as a double-edged sword in AMI, potentially participating in the occurrence and development of AMI by promoting inflammatory cytokine secretion and influencing atherosclerotic plaque, while also participating in myocardial remodeling and protecting myocardium from ischemia-reperfusion injury. However, the exploratory nature of these analyses necessitates further large-scale clinical sample analyses and experiments to quantify the above conclusions.
Visfatin and Hypertension
Hypertension, a major CVD risk factor, necessitates effective blood pressure control. Visfatin plays a significant role in hypertension pathology, evidenced by elevated plasma levels in refractory hypertensive patients. Antihypertensive therapy reduces visfatin levels, suggesting its association with blood pressure control. Moreover, visfatin's protective role in blood pressure regulation is evidenced by its downregulation in hypertensive patients and animals, alleviating endothelial dysfunction, smooth muscle proliferation, and extracellular matrix rearrangement. Visfatin/NAMPT emerges as a potential biomarker and therapeutic target for hypertension, although controversies persist regarding its circulatory levels and impact on patients, necessitating extensive observations and mechanistic studies.
Visfatin and Atrial Fibrillation (AF)
AF is a prevalent clinical arrhythmia, with its incidence increasing annually, leading to embolic events, elevated mortality rates, and decreased quality of life. Visfatin/NAMPT may contribute to AF onset, as AF patients typically have higher visfatin levels. researchers demonstrated in mice that NAMPT knockout enhances RyR2 gene phosphorylation, promoting diastolic calcium leakage in atrial myocytes, a precursor to AF. Therefore, regulating NAMPT could potentially mitigate AF occurrence. Obstructive sleep apnea (OSA) is a recognized clinical risk factor for AF, exacerbating symptoms and complicating treatment. Visfatin concentration correlates positively with OSA severity, likely due to intermittent hypoxia-induced sympathetic stimulation and endothelial dysfunction. Targeting visfatin to reduce OSA risk warrants investigation for AF prevention or management. Additionally, visfatin influences AF treatment outcomes, as pericardial fat in AF patients exhibits high glucose metabolism and inflammation, with visfatin mediating cytokine production and oxidative stress.
In summary, visfatin, a new adipokine, has diverse functions in the body and is involved in various processes like metabolism and inflammation. It protects against cardiovascular diseases by improving endothelial function and inhibiting inflammation, but high levels may worsen atherosclerosis. Further research is needed to fully understand its role in different cardiovascular conditions, offering potential for targeted therapies in the future.
References
- Dakroub A., et al. Visfatin: An emerging adipocytokine bridging the gap in the evolution of cardiovascular diseases. Journal of Cellular Physiology. 2021, 236(9): 6282-96.
- Dakroub A., et al. Visfatin: A possible role in cardiovasculo-metabolic disorders. Cells. 2020, 9(11): 2444.
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