Highlights
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Context-dependent protective and harmful effects of SIRT2 in various cardiovascular pathologies, including hypertrophy and vascular dysfunction.
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SIRT2 is not solely a deacetylase but has diverse catalytic activities, each with important roles in cardiovascular health.
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SIRT2 has knowledge gaps in its mechanisms of action in the cardiovascular system; the other Sirtuin isoforms do not.
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Uniting our understanding of SIRT2′s context-dependent roles and unique catalytic activities will undermine its therapeutic potential.
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To guide therapeutic interventions towards cardiovascular development, aging, and disease by filling research gaps on SIRT2 activities.
Abstract
Cardiovascular diseases (CVDs) are leading causes of mortality throughout the world, and hence, there is a critical need to elucidate their molecular mechanisms. The Sirtuin (SIRT) family of NAD+-dependent enzymes has recently been shown to play a critical role in cardiovascular health and disease, and several SIRT isoforms, especially SIRT1 and SIRT3, have been amply investigated. However, the precise function of SIRT2 is only partially explored. Here, we review the current understanding of the involvement of SIRT2 in various cardiovascular pathologies, such as cardiac hypertrophy, ischemia-reperfusion injury, diabetic cardiomyopathy, and vascular dysfunction, with emphasis placed on the context-dependent protective or deleterious actions of SIRT2, including its wide array of catalytic activities which span beyond deacetylation. Furthermore, the review uncovers several unresolved research gaps for SIRT2 mechanisms by which SIRT2 modulates cardiac and vascular function during development and aging, thereby paving the way for the discovery of novel therapeutic targets as well as SIRT2-targeted interventions in the prevention and treatment of various cardiovascular diseases.
Introduction
Cardiovascular diseases (CVDs) are the leading cause of death globally. Notably, aging is one of the most significant risk factors for developing CVDs, as the prevalence and mortality from these diseases tend to increase with age. While various molecular changes occur during aging, deregulation of the NAD+/NADH pool is considered a defining characteristic of aging. , The decline in NAD+ levels is associated with the development of several CVDs, such as cardiac hypertrophy and heart failure. In contrast, supplementation of NAD+ has been shown to improve cardiac function. Interestingly, the beneficial effects of NAD+ supplementation in the heart are mediated by a family of NAD+-dependent enzymes called sirtuins. Sirtuins are post-translational modification enzymes with diverse histone and non-histone targets. , There are seven mammalian sirtuins, which are distributed primarily in three subcellular compartments: the cytoplasm (SIRT1, SIRT2), nucleus (SIRT1, SIRT6, SIRT7), and mitochondria (SIRT3, SIRT4, SIRT5). , Sirtuins regulate various physiological processes, including metabolism, oxidative stress, DNA repair, protein synthesis, inflammation, and cell death. Due to their critical dependence on NAD+, sirtuins function closely links energy metabolism and cellular function. Sirtuins also play a vital role in the cardiovascular system and have been implicated in the pathogenesis of cardiac hypertrophy, fibrosis, ischemia-reperfusion injury, diabetic cardiomyopathy, endothelial dysfunction, and heart failure. The roles of SIRT1, SIRT3, SIRT6, and SIRT7 in the cardiovascular system have been well studied, but relatively little is known about the regulation of cardiovascular physiology and pathology by the cytoplasmic SIRT2, despite its crucial roles in diverse cellular processes. ,
SIRT2 is predominantly a cytoplasmic protein but can also localize to the nucleus under specific conditions. In cardiomyocytes, SIRT2 is found in the cytoplasm under both basal and stressed conditions. , Of the three major SIRT2 isoforms detected,22 isoforms 1 (∼43 kDa) and 2 (∼39 kDa) exhibit robust deacetylase activity. In contrast, isoform 5 (∼36 kDa) does not exhibit deacetylase activity towards established SIRT2 substrates but can still interact with them. SIRT2 catalyzes the removal of acetyl groups from target proteins using an NAD+-dependent mechanism ( Fig. 1 ). In addition to deacetylation, SIRT2 can remove other acyl groups, such as 4-oxononanoyl, myristoyl, crotonyl, and benzoyl ( Fig. 2 ). SIRT2 regulates multiple cellular functions through these catalytic activities, including mitosis, cell differentiation, stress response, cellular survival, and homeostasis. thus playing an important role in both health and disease.
In this review, we discuss the recent advances in understanding the functions of SIRT2 in the cardiovascular system. Specifically, we explore the roles of SIRT2 in various pathologies, such as cardiac hypertrophy, oxidative stress, diabetic cardiomyopathy, and vascular function, along with the associated molecular mechanisms. Furthermore, we highlight the diverse catalytic activities of SIRT2 and the potential for using pharmacological inhibitors to study SIRT2 function in the heart. Finally, we identify some exciting unanswered questions about the possible roles of SIRT2 in the heart, which could inspire new research directions in this field.
The Sirtuin family: emerging roles in cardiovascular health and disease
Sirtuins (SIRTs) are a broad family of NAD+-dependent enzymes found in all organisms, from bacteria to humans. Sir4 was identified as a critical regulator of replicative lifetime, whereas the other five SIRTs were initially described in yeast as histone deacetylases that suppress transcription. Cellular senescence may be influenced by Sir2′s deacetylase activity, which regulates NAD+ levels. Like Sir2, the SIRT protein family in mammals includes seven deacetylases (SIRT1-7), all of which have been shown to play an important role in the development of cardiovascular disease. , ,
The SIRT1-7 core domain uses NAD+ as a cosubstrate and is well conserved. The structural differences between an enzyme’s N- and C-terminal sections lead to various substrate specificities, subcellular localizations, and enzymatic activity. The SIRT family shows cellular selectivity in both expression and localization. The cytoplasm contains SIRT1 and SIRT2, the mitochondria SIRT3, SIRT4, and SIRT5, and the nucleus SIRT1, SIRT6, and SIRT7. These proteins contribute to the epigenetic regulation of cellular phenotypes. Large-scale investigations on CVD have focused on SIRT1, indicating that its role in modulating vascular tone is connected to several molecular signaling pathways required for optimal vascular function. SIRT1 regulates physiological processes, including heart oxidative stress, cell death, and senescence. SIRT7 proteins have been identified as contributing to cardiac ischemia-reperfusion damage and cardiomyocyte death. The early investigations on SIRT2 focused mostly on controlling cellular senescence. The mitochondria-specific deacetylases SIRT3, SIRT4, and SIRT5 feature a mitochondrial signal sequence at the N-terminus. They facilitate metabolic regulation coordination. SIRT activation or regulation is a feedback loop against various stimuli and possible therapeutic targets for age-related disorders, including cardiovascular disease.
SIRTs are a prospective therapeutic target for preventing and treating cardiovascular disorders by targeted pharmaceutical therapies. Most research has focused on SIRT1-activating compounds (STACs), such as resveratrol, SRT1460, SRT1720, and SRT2183. Recent research has concentrated on novel small-molecule SIRT agonists such as UBCS039, MDL-800, quercetin, and lutein. SIRT inhibitors, such as EX-527, have been proven in animal models of fibrosis caused by a high-fat diet to slow disease progression by increasing SIRT4 expression. The SIRT protein family has attracted significant attention in cardiovascular disease research due to its essential function in regulating histone deacetylation. SIRTs function not only as histone deacetylases but also as mono-ADP-ribosyl transferases and possess other non-histone deacetylase functions. These functions are crucial for cardiovascular diseases, as shown in Fig. 1 . SIRTs affect the progression and manifestation of cardiovascular diseases by modulating essential pathogenic mechanisms, including cell proliferation, senescence, DNA damage, inflammation, oxidative stress, and cellular metabolism. The discovery of SIRT-targeting medications has the potential to lead to the development of new therapeutic approaches.
SIRT2: A multifaceted regulator in cardiovascular health and disease
The silent information regulators (SIRT) family is a gene sink initially discovered in yeast protein. SIRT2 belongs to a class of enzymes called nicotinamide adenine dinucleotide (NAD+)-dependent deacetylases that control key signaling pathways in simple and complex life forms. There are seven versions of these proteins in mammals, and they are called SIRT1 through SIRT7 because the proteins each interact with (and where the proteins are in the cell) are different. SIRT3, SIRT4, and SIRT5 are mitochondrial enzymes, whereas SIRT1, SIRT6, and SIRT7 are nuclear enzymes. Unlike other SIRTs, SIRT2 is not known to be chromatin-associated. SIRT2, however, residing in the nucleus during the G2/M phase of cell division, can modify histone H4K16 to decrease chromatin condensation and promote DNA replication.
Humans’ SIRT2 gene is located on chromosome 19. This gene is located on about 21 base pairs and encodes a protein of 389 amino acids and 17 exons. SIRT2 is found in many tissues and organs in the body and is most abundant in the heart, brain, ovary, esophagus, and adipose tissue. Several substrates of SIRT2, such as alpha-tubulin, p53, and FOXO proteins, have been documented to be modulated in transcriptional activity and protein levels by research. As a result, SIRT2 is critical for regulating oxidative stress, inflammatory responses, and cellular aging. It also has a major role in the cardiovascular system, including the development of diabetic cardiomyopathy, heart failure, and myocardial ischemia-reperfusion injury.
Function of SIRT2
SIRT2′s multifaceted antioxidant functions
Oxidative stress is a stress reaction that occurs when there is an imbalance between the generation of reactive oxygen species (ROS) and antioxidant defense, ultimately reducing cell viability. It has shown that SIRT2 deficiency strongly affects the heart cells with research. In particular, they discovered that H9c2 cardiomyocytes with fewer SIRT2 contained increased transcription factors, including NF-E2-related factor 2. At higher degrees of malondialdehyde (MDA), the activity of superoxide dismutase (SOD) and Nrf2 (a transcriptional regulator of oxidative stress and related enzymes) decreased, resulting in increased reactive oxygen species (ROS) and higher oxidative stress. These findings also demonstrated that reduced SIRT2 expression in the spinal cord following nerve injuries also impairs Nrf2 function, exacerbating the effects of oxidative stress. Second, another research group showed that SIRT2 is also involved in the deacetylation of bone morphogenetic protein 2 (BMP2), specifically in ex vivo rat femoral head necrosis induced by glucocorticoid. Specifically, this aids the protection of bone marrow-derived mesenchymal stem cells (BMSC) from oxidative stress damage in cancer contexts. In mouse heart cells, SIRT2 can deacetylate polyADP-ribose polymerase 1 (PARP1) and promote its ubiquitination and degradation, reducing oxidative stress damage to the heart. These findings indicate that SIRT2 is essential for reducing the footprint of oxidative stress on the nervous system, bone, and heart by regulating Nrf2 activity and deacetylating important substrates.
SIRT2′s complex regulation of inflammation
The body’s response to external threats, such as infections or injuries, is called inflammation. However, the disease can harm tissue instead of protecting it. Physiological inflammation, however, is a normal, essential process that protects health. Several studies have demonstrated that the down-regulation of SIRT2 can increase the phosphorylation and acetylation of p65, the activation of the nuclear factor kappa-B (NF-κB) signaling pathway, the induction of NF-κB-dependent inflammatory cytokines, and the development of airway inflammation and bronchial hyperreactivity in mice. SIRT2 deficiency has been observed to boost lipid deposition and inflammation in cells in mice with nonalcoholic steatohepatitis, which leads to intestinal flora aggregation and elevated acetylation factors in animals, which in turn makes the disease process worse. Other investigations discovered this. Additionally, the deletion of SIR in the transgenic mouse model of Alzheimer’s disease (AD) leads to an increase in the production of pro-inflammatory cytokines, which in turn encourages the development of several other inflammatory disorders. On the other hand, recent research has shown that SIRT2 is strongly expressed in people with calcific aortic valve disease (CAVD), further exacerbating the inflammation in the heart. However, SIRT2 overexpression in human cardiomyocytes promotes cardiac inflammation, which differences between different species and the degree and type of body system tolerance to stimulation may cause. The studies above demonstrated that SIRT2 significantly inhibits airway inflammation, hepatitis, and neuroinflammation in mice. It is, therefore, necessary to do additional research using a variety of species better to understand the function of SIRT2 in myocardial inflammation.
A key regulator of cellular senescence and cardiac aging
The term “cell senescence” describes the permanent cessation of the stable cell cycle brought on by internal and external factors. This standstill is marked by alterations in metabolic processes and secretory characteristics. When mesenchymal stem cells (MSC) were pre-treated with macrophage migration inhibitory factor (MIF), it was discovered that the exosomes generated by SIRT2 could activate the protective impact of SIRT2 on the heart, slow down the aging process of cardiomyocytes, and consequently improve the cardiac function of mice. With modified aging regulatory protein p66Shc, SIRT2 can prevent p66Shc from activating in aged mouse models, lowering heart inflammation and improving heart cell aging. SIRT2 deficiency also increased acetylation in primates’ signal transducer and activator of the transcription 3 (STAT3) region. The result is that heart cells rapidly become thrown out of whack because of malfunctioning a cyclin-dependent kinase inhibitor called CDKN2B, which furthers the harmful process of aging heart cells. SIRT2 plays a fundamental role in balancing heart cell aging with substrate deacetylation, suggesting SIRT2 is a therapeutic target for human cardiac aging and age-related cardiovascular diseases.
SIRT2 and cardiovascular disease
SIRT2 is widely distributed throughout the cardiovascular system, especially in heart muscle cells, vascular endothelial cells, and atherosclerotic plaques. It is an important player in the regulation and homeostasis of cardiometabolic mechanisms, which are the pathological and physiological processes related to cardiovascular disease.
Key mediators of cardiac hypertrophy and fibrosis
Cardiac hypertrophy is a common adaptive response to pressure or volume load on the heart. When the heart muscle expands, as a protective mechanism, this area of the heart muscle tries to help the heart function normally and reduce tension on the ventricular walls. Nevertheless, prolonged cardiac hypertrophy eventually culminates in maladaptive remodeling and the development of heart failure, for which there are no effective treatment options. The critical importance of understanding the molecular processes of myocardial hypertrophy and fibrosis has led to much research investigating the role of Sirtuin (SIRT) proteins in this context. We have described previously that the SIRT family of NAD+-dependent enzymes is involved in the development of cardiovascular disease. Besides serving the general functions of SIRTs to modulate vascular homeostasis, cell senescence, oxidative stress, and other related cardiovascular health processes, the different SIRT isoforms have been found to possess species and expression-specific roles in the setting of cardiac hypertrophy as shown in Fig. 2 .
Pathological myocardial hypertrophy is an adaptive change through which the heart resists a series of pathological stimuli. This change is associated with an increase in the volume of cardiomyocytes and myocardial fibrosis and with apoptosis and necrosis of cardiomyocytes. This decreases cardiac compliance and heart failure. In the case of abnormal cardiac hypertrophy, it has been discovered that SIRT2 functions as a cardioprotective deacetylase. In a mouse model of pathological cardiac hypertrophy caused by angiotensin II (Ang II), a lack of SIRT2 limits the movement of liver kinase B1 (LKB1) from the nucleus to the cytoplasm. It reduces the amount of phosphorylation that LKB1 produces. There was a decrease in the synthesis of adenosine 5′-monophosphate (AMP)–activated protein kinase (AMPK), which led to an increase in pathological cardiac hypertrophy in mice. Therefore, activating the LKB1-AMPK pathway by cardiomyocyte SIRT2 may benefit the protection of heart function. Other researchers have discovered that SIRT2 functions as an endogenous negative regulator of the nuclear factor of activated T cells (NFAT) transcription factor in mouse cardiomyocytes that have been knocked out of SIRT2. Furthermore, the deletion of SIRT2 can stabilize NFAT and improve NFAT nuclear localization. Increase the transcriptional activity of NFAT, leading to pathological hypertrophy of the heart. It has been proved for the first time that inhibition of SIRT2 expression in a mouse model of myocardial hypertrophy could promote constitutive photomorphogenesis9 signalosome 6. Constitutive photomorphogenesis9 signalosome 6, The interaction of CSN6) further aggravated Ang II-induced myocardial hypertrophy, significantly weakened myocardial contraction and diastole, and seriously affected the cardiac function of mice. In conclusion, activation of SIRT2 can protect the morphology of the myocardium by controlling the amounts of transcription factors.
It was discovered that in Ang II-induced mouse myocardial hypertrophy model and human hypertrophic heart, PHF19 (PHD finger protein 19, PhD finger protein 19, PhD finger protein 19, PhD finger protein 19, PhD finger protein 19, PhD finger protein 19, PhD finger protein 19, PhD finger protein 19, PHF19) induced histone three lysine 36 trimethylation by epigenetic inhibition of SIRT2 expression. This was accomplished by inhibiting the expression of SIRT2. Increasing the expression of atrial natriuretic peptides (ANP) and brain natriuretic peptides (BNP) leads to increased heart weight and cardiomyocyte size, ultimately resulting in pathological cardiac hypertrophy. H3K36me3) three methylation and histone H3 lysine 27 (histone lysine 27 trimethylation 3, H3K27me3) imbalances are also associated with cardiac hypertrophy marker genes. In addition, SIRT2 promotes H3K27 deacetylation in the Gal-3 promoter area in mice with the galectin-3 (Gal-3) gene knocked out. This results in decreased in production of Gal-3, alleviating radiation-induced myocardial fibrosis and ultimately improving mice’s heart function. Several other studies have discovered that inhibiting microRNA-4731 (MIR-4731) can reduce SIRT2 and cyclin D1 in cardiac mast cell models that Ang II has stimulated. There is a correlation between the decreased expression level of CCND1 and cytochrome C (CYT-C) and the increased expression level of myocardial cell death, ultimately leading to worsening cardiac hypertrophy. According to the findings of these investigations, epigenetics, and microRNAs may control the expression of SIRT2, and they may also play a part in the development of cardiac hypertrophy. As a result, the investigation of particular SIRT2 agonists has the potential to improve significantly pathological cardiac hypertrophy, hence preventing the occurrence of myocardial remodeling.
SIRT2: A double-edged sword in diabetic cardiomyopathy
Diabetic cardiomyopathy (DCM) is a disease that is due to diabetes and manifests as systolic or diastolic dysfunction of the left ventricle. This dysfunction results in significant metabolic disorders and microvascular lesions, culminating in myocardial inflammation with cardiomyocyte necrosis and myocardial fibrosis, impacting cardiac function. In the myocardium, SIRT2 promotes the deacetylation of α-tubulin in individuals with type 1 diabetes mellitus (T1DM) induced by streptozotocin (also known as steroids). The RAGE signaling pathway is also activated, which worsens ventricular systolic function. Additionally, in diabetic rats, SIRT2 causes cardiomyocyte oxidative stress that further reduces mitochondrial function and cardiac systolic dysfunction. As a result, the inhibition of SIRT2 may play a protective role in the heart’s function in diabetic cardiomyopathy.
Feasibility for delaying the action potential duration of cardiomyocytes and decreasing myocardial contractility in the presence of diabetic SIRT2 expression inhibition in diabetic mice. Cardiac dysfunction would ensue, and diabetic cardiomyopathy incidence and progression would be promoted. Recently, we found that PALMITIC ACID (PA), HIGH GLUCOSE (HG) induced pro-death in human umbilical vein endothelial cells (HUVECs) by NOD-LIKE RECEPTOR PROTEIN 3 (NOD-LIKE RECEPTOR PROTEIN 3)-dependent deacetylations of NLRP3, mediated by SIRT2. Diabetic mice are less damaged by their blood vessels. These findings suggest that SIRT2 may serve as a beneficial myocardiocyte contractility regulatory factor in the presence of diabetic cardiomyopathy, as shown in Fig. 3 . However, the lack of study of many species kinds and the fundamental studies makes SIRT2 function in diabetic cardiomyopathy not fully understood yet. Hence, extra research should be directed towards such studies.
