Deacetylation of Septin4 by SIRT2 (Silent Mating Type Information Regulation 2 Homolog-2) Mitigates Damaging of Hypertensive Nephropathy.

BACKGROUND: Hypertension can lead to podocyte damage and subsequent apoptosis, eventually resulting in glomerulosclerosis. Although alleviating podocyte apoptosis has clinical significance for the treatment of hypertensive nephropathy, an effective therapeutic target has not yet been identified. The function of septin4, a proapoptotic protein and an important marker of organ damage, is regulated by post-translational modification. However, the exact role of septin4 in regulating podocyte apoptosis and its connection to hypertensive renal damage remains unclear. METHODS: We investigated the function and mechanism of septin4 in hypertensive nephropathy to discover a theoretical basis for targeted treatment. Mouse models including Rosa 26 (Gt(ROSA)26Sor)-SIRT2 (silent mating type information regulation 2 homolog-2)-Flag-TG (transgenic) (SIRT2-TG) mice SIRT2-knockout, and septin4-K174Q mutant mice, combined with proteomic and acetyl proteomics analysis, followed by multiple molecular biological methodologies, were used to demonstrate mechanisms of SIRT2-mediated deacetylation of septin4-K174 in hypertensive nephropathy. RESULTS: Using transgenic septin4-K174Q mutant mice treated with the antioxidant Tempol, we found that hyperacetylation of the K174 site of septin4 exacerbates Ang II (angiotensin II)- induced hypertensive renal injury resulting from oxidative stress. Proteomics and Western blotting assays indicated that septin4-K174Q activates the cleaved-PARP1 (poly [ADP-ribose] polymerase family, member 1)-cleaved-caspase3 pathway. In septin4-knockdown human renal podocytes, septin4-K174R, which mimics deacetylation at K174, rescues podocyte apoptosis induced by Ang II. Immunoprecipitation and mass spectrometry analyses identified SIRT2 as a deacetylase that interacts with the septin4 GTPase domain and deacetylates septin4-K174. In Sirt2-deficient mice and SIRT2-knockdown renal podocytes, septin4-K174 remains hyperacetylated and exacerbates hypertensive renal injury. By contrast, in Rosa26-Sirt2-Flag (SIRT2-TG) mice and SIRT2-knockdown renal podocytes reexpressing wild-type SIRT2, septin4-K174 is hypoacetylated and mitigates hypertensive renal injury. CONCLUSIONS: Septin4, when activated through acetylation of K174 (K174Q), promotes hypertensive renal injury. Septin4-K174R, which mimics deacetylation by SIRT2, inhibits the cleaved-PARP1-cleaved-caspase3 pathway. Septin4-K174R acts as a renal protective factor, mitigating Ang II-induced hypertensive renal injury. These findings indicate that septin4-K174 is a potential therapeutic target for the treatment of hypertensive renal injury.

The role of SMURFs in non-cancerous diseases.

The ubiquitin-proteasome system is a crucial mechanism for regulating protein levels in cells, with substrate-specific E3 ubiquitin ligases serving as an integral component of this system. Among these ligases are SMAD-specific E3 ubiquitin-protein ligase 1 (SMURF1) and SMAD-specific E3 ubiquitin-protein ligase 2 (SMURF2), which belong to the neural precursor cell-expressed developmentally downregulated 4 (NEDD4) subfamily of Homologous to E6-AP COOH terminus (HECT)-type E3 ligases. As E3 ligases, SMURFs have critical functions in regulating the stability of multiple proteins, thereby maintaining physiological processes such as cell migration, proliferation, and apoptosis. The occurrence of many diseases is attributed to abnormal cell physiology and an imbalance in cell homeostasis. It is noteworthy that SMURFs play pivotal roles in disease progression, with the regulatory functions being complex and either facilitative or inhibitory. In this review, we elucidate the mechanisms by which SMURF1 and SMURF2 can regulate disease progression in non-cancerous diseases. These significant findings offer potential novel therapeutic targets for various diseases and new avenues for research on SMURF proteins.

Down-regulation of WWP2 aggravates Type 2 diabetes mellitus-induced vascular endothelial injury through modulating ubiquitination and degradation of DDX3X.

BACKGROUND: Endothelial injury caused by Type 2 diabetes mellitus (T2DM) is considered as a mainstay in the pathophysiology of diabetic vascular complications (DVCs). However, the molecular mechanism of T2DM-induced endothelial injury remains largely unknown. Here, we found that endothelial WW domain-containing E3 ubiquitin protein ligase 2 (WWP2) act as a novel regulator for T2DM-induced vascular endothelial injury through modulating ubiquitination and degradation of DEAD-box helicase 3 X-linked (DDX3X). METHODS: Single-cell transcriptome analysis was used to evaluate WWP2 expression in vascular endothelial cells of T2DM patients and healthy controls. Endothelial-specific Wwp2 knockout mice were used to investigate the effect of WWP2 on T2DM-induced vascular endothelial injury. In vitro loss- and gain-of-function studies were performed to assess the function of WWP2 on cell proliferation and apoptosis of human umbilical vein endothelial cells. The substrate protein of WWP2 was verified using mass spectrometry, coimmunoprecipitation assays and immunofluorescence assays. The mechanism of WWP2 regulation on substrate protein was investigated by pulse-chase assay and ubiquitination assay. RESULTS: The expression of WWP2 was significantly down-regulated in vascular endothelial cells during T2DM. Endothelial-specific Wwp2 knockout in mice significantly aggravated T2DM-induced vascular endothelial injury and vascular remodeling after endothelial injury. Our in vitro experiments showed that WWP2 protected against endothelial injury by promoting cell proliferation and inhibiting apoptosis in ECs. Mechanically, we found that WWP2 is down-regulated in high glucose and palmitic acid (HG/PA)-induced ECs due to c-Jun N-terminal kinase (JNK) activation, and uncovered that WWP2 suppresses HG/PA-induced endothelial injury by catalyzing K63-linked polyubiquitination of DDX3X and targeting it for proteasomal degradation. CONCLUSION: Our studies revealed the key role of endothelial WWP2 and the fundamental importance of the JNK-WWP2-DDX3X regulatory axis in T2DM-induced vascular endothelial injury, suggesting that WWP2 may serve as a new therapeutic target for DVCs.

The role of SIRT2 in vascular-related and heart-related diseases: A review.

At present, cardiovascular disease is one of the important factors of human death, and there are many kinds of proteins involved. Sirtuins family proteins are involved in various physiological and pathological activities of the human body. Among them, there are more and more studies on the relationship between sirtuin2 (SIRT2) protein and cardiovascular diseases. SIRT2 can effectively inhibit pathological cardiac hypertrophy. The effect of SIRT2 on ischaemia-reperfusion injury has different effects under different conditions. SIRT2 can reduce the level of reactive oxygen species (ROS), which may help to reduce the severity of diabetic cardiomyopathy. SIRT2 can affect a variety of cardiovascular diseases, energy metabolism and the ageing of cardiomyocytes, thereby affecting heart failure. SIRT2 also plays an important role in vascular disease. For endothelial cell damage used by oxidative stress, the role of SIRT2 is bidirectional, which is related to the degree of oxidative stress stimulation. When the degree of stimulation is small, SIRT2 plays a protective role, and when the degree of stimulation increases to a certain level, SIRT2 plays a negative role. In addition, SIRT2 is also involved in the remodelling of blood vessels and the repair of skin damage.

The E3 ubiquitin ligase Smurf2 regulates PARP1 stability to alleviate oxidative stress-induced injury in human umbilical vein endothelial cells.

Oxidative stress injury is involved in many cardiovascular diseases, like hypertension and myocardial infarction. Ubiquitination is a ubiquitous protein post-translational modification that controls a wide range of biological functions and plays a crucial role in maintaining the homeostasis of cells in physiology and disease. Many studies have shown that oxidative stress damage is inextricably linked to ubiquitination. We demonstrate that Smurf2, an E3 ubiquitinated ligase, is involved in HUVEC apoptosis induced by oxidative stress to alleviate H2 O2 -induced reactive oxygen species (ROS) production and the apoptosis of human umbilical vein endothelial cells (HUVECs). At the same time, we found that Smurf2 can bind the poly(ADP-ribose) polymerase-1(PARP1), and the interaction is enhanced under the stimulation of oxidative stress. We further study and prove that Smurf2 can promote PARP1 ubiquitination and degradation. Collectively, we demonstrate Smurf2 degradation of overactivated PARP1 by ubiquitin-proteasome pathway to protect HUVEC and alleviate oxidative stress injury.

WWP2 protects against sepsis-induced cardiac injury through inhibiting cardiomyocyte ferroptosis.

Background and Objectives: Cardiac injury plays a critical role in contributing to the mortality associated with sepsis, a condition marked by various forms of programmed cell deaths. Previous studies hinted at the WW domain-containing E3 ubiquitin protein ligase 2 (WWP2) involving in heart failure and endothelial injury. However, the precise implications of WWP2 in sepsis-induced cardiac injury, along with the underlying mechanisms, remain enigmatic. Methods: Sepsis induced cardiac injury were constructed by intraperitoneal injection of lipopolysaccharide. To discover the function of WWP2 during this process, we designed and performed loss/gain-of-function studies with cardiac-specific vectors and WWP2 knockout mice. Combination experiments were performed to investigate the relationship between WWP2 and downstream signaling in septic myocardium injury. Results: The protein level of WWP2 was downregulated in cardiomyocytes during sepsis. Cardiac-specific overexpression of WWP2 protected heart from sepsis induced mitochondrial oxidative stress, programmed cell death and cardiac injury, while knockdown or knockout of WWP2 exacerbated this process. The protective potency of WWP2 was predominantly linked to its ability to suppress cardiomyocyte ferroptosis rather than apoptosis. Mechanistically, our study revealed a direct interaction between WWP2 and acyl-CoA synthetase long-chain family member 4 (FACL4), through which WWP2 facilitated the ubiquitin-dependent degradation of FACL4. Notably, we observed a notable reduction in ferroptosis and cardiac injury within WWP2 knockout mice after FACL4 knockdown during sepsis. Conclusions: WWP2 assumes a critical role in safeguarding the heart against injury induced by sepsis via regulating FACL4 to inhibit LPS-induced cardiomyocytes ferroptosis.

Cathepsin D Attenuates the Proliferation of Vascular Smooth Muscle Cells Induced by the AGE/RAGE Pathway by Suppressing the ERK Signal.

BACKGROUND: In this study, we aimed to clarify the role and mechanism by which Cathepsin D (CTSD) mediates the advanced glycation end products (AGEs)-induced proliferation of vascular smooth muscle cells (VSMCs). METHODS: We conducted a Western blotting assay and co-immunoprecipitation assay to detect the expression of target proteins and the interaction between different proteins. Cell Counting Kit-8 (CCK-8) assay and 5- ethynyl-2'-deoxyuridine (EdU) were used to evaluate the proliferation. RESULTS: AGEs significantly promoted phenotypic switching and proliferation of VSMCs in a concentration-dependent manner. This effect of AGEs was accompanied by inhibition of CTSD. Both the proliferation of VSMCs and inhibition of CTSD induced by AGEs could be attenuated by the specific inhibitor of the receptor for advanced glycation end products (RAGE), FPS-ZM1. Overexpression of CTSD significantly alleviated these effects of AGEs on VSMCs. The mechanism of CTSD action in VSMCs was also explored. Overexpression of CTSD reduced the activation of p-ERK caused by AGEs. By contrast, the knockdown of CTSD, elicited using a plasmid containing short hairpin RNA (shRNA) against CTSD, further increased the activation of p-ERK compared to AGEs alone. Additionally, co-immunoprecipitation studies revealed an endogenous interaction between CTSD, a protease, and p-ERK, its potential substrate. CONCLUSION: It has been demonstrated that CTSD downregulates the level of phosphorylated ERK by degrading its target, and this interaction plays a critical role in the proliferation of VSMCs induced by the AGE/RAGE axis. These results provide a novel insight into the prevention and treatment of vascular complications in diabetes.

Atorvastatin rescues vascular endothelial injury in hypertension by WWP2-mediated ubiquitination and degradation of ATP5A.

As a widely used lipid-lowering drug in clinical practice, atorvastatin is widely recognized for its role in protecting vascular endothelium in the cardiovascular system. However, a clear mechanistic understanding of its action is lacking. Here, we found that atorvastatin counteracted angiotensin II-induced vascular endothelial injury in mice with hypertension. Mechanistically, atorvastatin up-regulated WWP2, a E6AP C-terminus (HECT)-type E3 ubiquitin ligase with an essential role in regulating protein ubiquitination and various biological processes, thereby rescuing vascular endothelial injury. By ubiquitinating ATP5A (ATP synthase mitochondrial F1 complex subunit alpha), WWP2 degraded ATP5A via the proteasome pathway, stabilizing Bcl-2/Bax in the mitochondrial pathway of apoptosis. Moreover, atorvastatin further ameliorated death of vascular endothelial cells and improved vascular endothelial functions under WWP2 overexpression, whereas WWP2 knockout abrogated these beneficial effects of atorvastatin. Furthermore, we generated endothelial cell-specific WWP2 knockout mice, and this WWP2-mediated mechanism was faithfully recapitulated in vivo. Thus, we propose that activation of a WWP2-dependent pathway that is pathologically repressed in damaged vascular endothelium under hypertension is a major mechanism of atorvastatin. Our findings are also pertinent to develop novel therapeutic strategies for vascular endothelial injury-related cardiovascular diseases.

α-myosin heavy chain lactylation maintains sarcomeric structure and function and alleviates the development of heart failure.

The sarcomeric interaction of α-myosin heavy chain (α-MHC) with Titin is vital for cardiac structure and contraction. However, the mechanism regulating this interaction in normal and failing hearts remains unknown. Lactate is a crucial energy substrate of the heart. Here, we identify that α-MHC undergoes lactylation on lysine 1897 to regulate the interaction of α-MHC with Titin. We observed a reduction of α-MHC K1897 lactylation in mice and patients with heart failure. Loss of K1897 lactylation in α-MHC K1897R knock-in mice reduces α-MHC-Titin interaction and leads to impaired cardiac structure and function. Furthermore, we identified that p300 and Sirtuin 1 act as the acyltransferase and delactylase of α-MHC, respectively. Decreasing lactate production by chemical or genetic manipulation reduces α-MHC lactylation, impairs α-MHC-Titin interaction and worsens heart failure. By contrast, upregulation of the lactate concentration by administering sodium lactate or inhibiting the pivotal lactate transporter in cardiomyocytes can promote α-MHC K1897 lactylation and α-MHC-Titin interaction, thereby alleviating heart failure. In conclusion, α-MHC lactylation is dynamically regulated and an important determinant of overall cardiac structure and function. Excessive lactate efflux and consumption by cardiomyocytes may decrease the intracellular lactate level, which is the main cause of reduced α-MHC K1897 lactylation during myocardial injury. Our study reveals that cardiac metabolism directly modulates the sarcomeric structure and function through lactate-dependent modification of α-MHC.

E3 ubiquitin ligases in the acute leukemic signaling pathways.

Acute leukemia is a common hematologic tumor with highly genetic heterogeneity, and many factors are involved in the pathogenesis and drug-resistance mechanism. Emerging evidence proves that E3 ubiquitin ligases participate in the acute leukemic signaling pathways via regulating substrates. This review summarized the E3 ligases which can affect the leukemic signal. It is worth noting that the abnormal signal is often caused by a deficiency or a mutation of the E3 ligases. In view of this phenomenon, we envisioned perspectives associated with targeted agonists of E3 ligases and proteolysis-targeting chimera technology. Moreover, we emphasized the significance of research into the upstream factors regulating the expression of E3 ubiquitin ligases. It is expected that the understanding of the mechanism of leukemic signaling pathways with which that E3 ligases are involved will be beneficial to accelerating the process of therapeutic strategy improvement for acute leukemia.

An unexpected role for BAG3 in regulating PARP1 ubiquitination in oxidative stress-related endothelial damage.

Oxidative stress-associated endothelial damage is the initiation factor of cardiovascular disease, and protein posttranslational modifications play critical roles in this process. Bcl-2-associated athanogene 3 (BAG3) is a molecular chaperone regulator of the BAG family, which interacts with various proteins and influences cell survival by activating multiple pathways. BAG3 undergoes posttranslational modifications; however, research evaluating BAG3 acetylation and its regulatory mechanism is lacking. In addition, the interacting protein and regulatory mechanism of BAG3 in oxidative stress-associated endothelial damage remain unclear. Here, key molecular interactions and protein modifications of BAG3 were identified in oxidative stress-associated endothelial damage. Endothelial-specific BAG3 knockout in the mouse model starkly enhances oxidative stress-associated endothelial damage and vascular remodeling, while BAG3 overexpression in mice significantly relieves this process. Mechanistically, poly(ADP-ribose) polymerase 1 (PARP1), causing oxidative stress, was identified as a novel physiological substrate of BAG3. Indeed, BAG3 binds to PARP1's BRCT domain to promote its ubiquitination (K249 residue) by enhancing the E3 ubiquitin ligase WWP2, which leads to proteasome-induced PARP1 degradation. Furthermore, we surprisingly found that BAG3 represents a new substrate of the acetyltransferase CREB-binding protein (CBP) and the deacetylase Sirtuin 2 (SIRT2) under physiological conditions. CBP/SIRT2 interacted with BAG3 and acetylated/deacetylated BAG3's K431 residue. Finally, deacetylated BAG3 promoted the ubiquitination of PARP1. This work reveals a novel regulatory system, with deacetylation-dependent regulation of BAG3 promoting PARP1 ubiquitination and degradation via enhancing WWP2, which is one possible mechanism to decrease vulnerability of oxidative stress in endothelial cells.

DNA Polymerase Gamma Recovers Mitochondrial Function and Inhibits Vascular Calcification by Interacted with p53.

DNA polymerase gamma (PolG) is the major polymerase of mitochondrial DNA (mtDNA) and essential for stabilizing mitochondrial function. Vascular calcification (VC) is common senescence related degenerative pathology phenomenon in the end-stage of multiple chronic diseases. Mitochondrial dysfunction was often observed in calcified vessels, but the function and mechanism of PolG in the calcification process was still unknown. The present study found PolGD257A/D257A mice presented more severe calcification of aortas than wild type (WT) mice with vitamin D3 (Vit D3) treatment, and this phenomenon was also confirmed in vitro. Mechanistically, PolG could enhance the recruitment and interaction of p53 in calcification condition to recover mitochondrial function and eventually to resist calcification. Meanwhile, we found the mutant PolG (D257A) failed to achieve the same rescue effects, suggesting the 3'-5' exonuclease activity guarantee the enhanced interaction of p53 and PolG in response to calcification stimulation. Thus, we believed that it was PolG, not mutant PolG, could maintain mitochondrial function and attenuate calcification in vitro and in vivo. And PolG could be a novel potential therapeutic target against calcification, providing a novel insight to clinical treatment.

Comprehensive Bioinformatics Analysis Identifies POLR2I as a Key Gene in the Pathogenesis of Hypertensive Nephropathy.

Hypertensive nephropathy (HN), mainly caused by chronic hypertension, is one of the major causes of end-stage renal disease. However, the pathogenesis of HN remains unclarified, and there is an urgent need for improved treatments. Gene expression profiles for HN and normal tissue were obtained from the Gene Expression Omnibus database. A total of 229 differentially co-expressed genes were identified by weighted gene co-expression network analysis and differential gene expression analysis. These genes were used to construct protein-protein interaction networks to search for hub genes. Following validation in an independent external dataset and in a clinical database, POLR2I, one of the hub genes, was identified as a key gene related to the pathogenesis of HN. The expression level of POLR2I is upregulated in HN, and the up-regulation of POLR2I is positively correlated with renal function in HN. Finally, we verified the protein levels of POLR2I in vivo to confirm the accuracy of our analysis. In conclusion, our study identified POLR2I as a key gene related to the pathogenesis of HN, providing new insights into the molecular mechanisms underlying HN.

Deacetylation-dependent regulation of PARP1 by SIRT2 dictates ubiquitination of PARP1 in oxidative stress-induced vascular injury.

Poly(ADP-ribose) polymerase 1 (PARP1) has a major regulatory role in cardiovascular disease. However, inhibiting PARP1 activity does not significantly improve clinical outcomes of cardiovascular disease, which suggests that the regulatory mechanism of PARP1 in cardiovascular disease is unclear. Here, we focused on deacetylation regulatory mechanisms of PARP1 and crosstalk of PARP1 post-translational modifications. We uncovered the crucial molecular interactions and protein modifications of deacetylase Sirtuin 2 (SIRT2) and PARP1 in vascular damage. The results showed that SIRT2 was involved in this process and oxidative stress damage factor PARP1 was a novel physiological substrate of SIRT2. SIRT2 interacted with PARP1 at the PARP-A-helical domain and deacetylated the K249 residue of PARP1. Furthermore, SIRT2 promoted ubiquitination of the K249 residue of PARP1 via mobilization of the E3 ubiquitin ligase WW domain-containing protein 2 (WWP2), which led to proteasome-mediated degradation of PARP1. Knockout of SIRT2 in mice and cells increased PARP1 acetylation and decreased PARP1 ubiquitination, which in turn aggravated oxidative stress-induced vascular injury and remodeling. Conversely, overexpression of SIRT2 in mice and cells decreased PARP1 acetylation, increased PARP1 ubiquitination, and relieved oxidative stress-induced vascular injury and remodeling. Overall, this study revealed a previously unrecognized mechanistic link between SIRT2 and PARP1 in the regulation of oxidative stress-induced vascular injury.

The deacetylation-phosphorylation regulation of SIRT2-SMC1A axis as a mechanism of antimitotic catastrophe in early tumorigenesis.

Improper distribution of chromosomes during mitosis can contribute to malignant transformation. Higher eukaryotes have evolved a mitotic catastrophe mechanism for eliminating mitosis-incompetent cells; however, the signaling cascade and its epigenetic regulation are poorly understood. Our analyses of human cancerous tissue revealed that the NAD-dependent deacetylase SIRT2 is up-regulated in early-stage carcinomas of various organs. Mass spectrometry analysis revealed that SIRT2 interacts with and deacetylates the structural maintenance of chromosomes protein 1 (SMC1A), which then promotes SMC1A phosphorylation to properly drive mitosis. We have further demonstrated that inhibition of SIRT2 activity or continuously increasing SMC1A-K579 acetylation causes abnormal chromosome segregation, which, in turn, induces mitotic catastrophe in cancer cells and enhances their vulnerability to chemotherapeutic agents. These findings suggest that regulation of the SIRT2-SMC1A axis through deacetylation-phosphorylation permits escape from mitotic catastrophe, thus allowing early precursor lesions to overcome oncogenic stress.

Role of WW domain E3 ubiquitin protein ligase 2 in modulating ubiquitination and Degradation of Septin4 in oxidative stress endothelial injury.

Oxidative stress-associated endothelial injury is the initial event and major cause of multiple cardiovascular diseases such as atherosclerosis and hypertensive angiopathy. A protein homeostasis imbalance is a critical cause of endothelial injury, and homologous to E6AP C-terminus (HECT)-type E3 ubiquitin ligases are the core factors controlling protein homeostasis. Although HECT-type E3 ubiquitin ligases are involved in the regulation of cardiac development and diseases, their roles in endothelial injury remain largely unknown. This study aimed to identify which HECT-type E3 ubiquitin ligase is involved in endothelial injury and clarify the mechanisms at molecular, cellular, and organism levels. We revealed a novel role of the HECT-type E3 ubiquitin ligase WWP2 in regulating endothelial injury and vascular remodeling after endothelial injury. Endothelial/myeloid-specific WWP2 knockout in mice significantly aggravated angiotensin II/oxidative stress-induced endothelial injury and vascular remodeling after endothelial injury. The same results were obtained from in vitro experiments. Mechanistically, the endothelial injury factor Septin4 was identified as a novel physiological substrate of WWP2. In addition, WWP2 interacted with the GTPase domain of Septin4, ubiquitinating Septin4-K174 to degrade Septin4 through the ubiquitin-proteasome system, which inhibited the Septin4-PARP1 endothelial damage complex. These results identified the first endothelial injury-associated physiological pathway regulated by HECT-type E3 ubiquitin ligases in vivo as well as a unique proteolytic mechanism through which WWP2 controls endothelial injury and vascular remodeling after endothelial injury. These findings might provide a novel treatment strategy for oxidative stress-associated atherosclerosis and hypertensive vascular diseases.

Structure and Function of HECT E3 Ubiquitin Ligases and their Role in Oxidative Stress.

Ubiquitination is a modification after protein transcription that plays a vital role in maintaining the homeostasis of the cellular environment. The Homologous to E6AP C-terminus (HECT) family E3 ubiquitin ligases are a kind of E3 ubiquitin ligases with a C-terminal HECT domain that mediates the binding of ubiquitin to substrate proteins and a variable-length N-terminal extension. HECT-ubiquitinated ligases can be divided into three categories: NEDD4 superfamily, HERC superfamily, and other HECT superfamilies. HECT ubiquitin ligase plays an essential role in the development of many human diseases. In this review, we focus on the physiological and pathological processes involved in oxidative stress and the role of E3 ubiquitin ligase of the HECT family.

The Role of Mitochondria in Vascular Calcification.

Vascular calcification (VC) was defined as the ectopic deposition of calcium-phosphorus complexes on the blood vessel walls. It was a process involving multiple factors and mechanisms, covering the phenotype transition of vascular smooth muscle cells (VSMCs) and release of microvesicles. It was a common end-stage alteration of chronic diseases such as cardiovascular disease and chronic kidney disease. Increasing evidence indicates that mitochondria were involved in the development of VC. Mitochondria provided energy to cells, maintained the stability of cell functions, and participated in a variety of biological behavior. Oxidative stress, autophagy, apoptosis, and mitochondrial DNA (mtDNA) damage could affect the development of VSMCs calcification by alteration of mitochondrial function. This article reviewed the mechanism of calcification and the role of mitochondria in VC, aiming to raise a novel insight into drug development and clinical treatment.

E3 Ubiquitin ligase NEDD4 family­regulatory network in cardiovascular disease.

Protein ubiquitination represents a critical modification occurring after translation. E3 ligase catalyzes the covalent binding of ubiquitin to the protein substrate, which could be degraded. Ubiquitination as an important protein post-translational modification is closely related to cardiovascular disease. The NEDD4 family, belonging to HECT class of E3 ubiquitin ligases can recognize different substrate proteins, including PTEN, ENaC, Nav1.5, SMAD2, PARP1, Septin4, ALK1, SERCA2a, TGFßR3 and so on, via the WW domain to catalyze ubiquitination, thus participating in multiple cardiovascular-related disease such as hypertension, arrhythmia, myocardial infarction, heart failure, cardiotoxicity, cardiac hypertrophy, myocardial fibrosis, cardiac remodeling, atherosclerosis, pulmonary hypertension and heart valve disease. However, there is currently no review comprehensively clarifying the important role of NEDD4 family proteins in the cardiovascular system. Therefore, the present review summarized recent studies about NEDD4 family members in cardiovascular disease, providing novel insights into the prevention and treatment of cardiovascular disease. In addition, assessing transgenic animals and performing gene silencing would further identify the ubiquitination targets of NEDD4. NEDD4 quantification in clinical samples would also constitute an important method for determining NEDD4 significance in cardiovascular disease.

The Role of BRG1 in Antioxidant and Redox Signaling.

Redox homeostasis is regulated by critical molecules that modulate antioxidant and redox signaling (ARS) within the cell. Imbalances among these molecules can lead to oxidative stress and damage to cell functions, causing a variety of diseases. Brahma-related gene 1 (BRG1), also known as SMARCA4, is the central ATPase catalytic subunit of the switch/sucrose nonfermentable (SWI/SNF) chromatin remodeling complex, which plays a core role in DNA replication, repair, recombination, and transcriptional regulation. Numerous recent studies show that BRG1 is involved in the regulation of various cellular processes associated with ARS. BRG1, as a major factor in chromatin remodeling, is essential for the repair of oxidative stress-induced DNA damage and the activation of antioxidant genes under oxidative stress. Consequently, a comprehensive understanding of the roles of BRG1 in redox homeostasis is crucial to understand the normal functioning as well as pathological mechanisms. In this review, we summarized and discussed the role of BRG1 in the regulation of ARS.