Abstract Acute lymphoblastic leukemia (ALL) has been huge threaten for people health and finding effective target therapy is urgent and important. WWP2, as one of E3 ubiquitin ligase, is involved in many biological processes by specifically binding to substrates. PARP1 plays a role in cell apoptosis and is considered as a therapeutic target of certain cancers. In this study, we firstly tested WWP2 expression in patients and normal people and analyzed the relationship with clinicopathologic factors. We demonstrated WWP2 was involved in ALL apoptosis and knockout WWP2 alleviated ALL apoptosis induced by Dox in vitro and vivo. WWP2 negatively regulated and interacted with PARP1 in vitro and vivo and WWP2 mechanically degraded PARP1 through polyubiquitin-proteasome pathway. These findings suggested WWP2 played a role in ALL apoptosis and displayed a regulatory pathway of PARP1, which provide a new potential therapeutic target for the treatment of ALL.
Abstract Septin4, a protein localized at mitochondrion, can promote cells apoptosis mainly by binding XIAP (X-linked inhibitors of apoptosis), however, nothing is known about the role and mechanism of Septin4 in cardiomyocytes apoptosis. Here in the current study, we report that HIF-1α (hypoxia-inducible factor 1 alpha) is a novel interacting protein with Septin4 at Septin4-GTPase domain. In addition, Septin4 enhances the binding between HIF-1α and the E3 ubiquitin ligase VHL (von Hippel-Lindau protein) to down-regulate HIF-1α, and by reducing cardio-protective factor HIF-1α levels, Septin4 aggravated the hypoxia-induced cardiomyocytes apoptosis. We believe these findings will be beneficial to provide effective strategies for clinical treatment of myocardial ischemia and the subsequent injury caused by myocardial hypoxia.
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.
SIRT1 and STAT3 are key to human aortic vascular smooth muscle cells (HAVSMCs) proliferation, migration and phenotypic transformation, but the regulatory mechanism of SIRT1-STAT3 in this process is still unclear.Septin4 is a cytoskeleton-related protein that regulates oxidative stress-vascular endothelial injury.However, the role and underlying mechanism of Septin4 in atherosclerosis remains unknown.Here, we revealed the role and mechanism of Septin4 in regulating SIRT1-STAT3 in atherosclerosis.We determined that the expression of Septin4 were markedly increased in Apoe -/-atherosclerosis mice and PDGF-BB-induced HAVSMCs.Knockdown of Septin4 significantly increased PDGF-BB-induced HAVSMCs proliferation, migration and phenotypic transformation, while overexpression of Septin4 had the opposite effects.Mechanically, co-immunoprecipitation results demonstrated that Septin4 was a novel interacting protein of STAT3 and SIRT1.Septin4 formed a complex with SIRT1-STAT3, enhancing the interaction between SIRT1 and STAT3, ensuing promoting SIRT1-regulated STAT3-K685 deacetylation and STAT3-Y705 dephosphorylation, which inhibited PDGF-BB-induced HAVSMCs proliferation, migration and phenotype transformation.Therefore, our findings provide novel insights into the prevention and treatment of atherosclerosis.
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.
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.
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.
High systolic blood pressure (HSBP) can cause adverse cardiovascular events and is therefore associated with a heavy global disease burden. However, this disease burden is poorly understood in youth and young adults. We aimed to explore this population to better understand the evolving trends in HSBP-related disease burden, which is crucial for effectively controlling and mitigating harmful effects. This systematic analysis used data from the 2021 Global Burden of Disease Study, spanning 1990–2021. Participants were aged 15–39 years from 204 countries/territories. We analysed HSBP-related disease burden by region, sex, age, and temporal trends. The primary outcomes were disability-adjusted life years (DALYs), mortality rates, and estimated annual percentage change. Globally, the number of HSBP-related deaths among youth and young adults has increased by 36.11% (95% uncertainty interval [95% UI], 20.96–52.37%), whereas the number of DALYs has increased by 37.68% (95% UI, 22.69–53.65%); however, global mortality and DALY rates have remained relatively stable. In 2021, the mortality and DALY rates were 4.29 (95% UI, 3.29–5.28) and 263.37 (95% UI, 201.40–324.46) per 100,000 population, respectively. The overall HSBP-related burden was higher in males than in females, with increasing and decreasing trends for males and females, respectively. Regionally, significant improvements in HSBP-related burden were observed in most high-sociodemographic index (SDI) regions, including high-income Asia Pacific (deaths: percentage change, − 72.65%; DALYs: percentage change, − 69.30%) and Western Europe (deaths: percentage change, − 72.89%; DALYs: percentage change, − 67.48%). In contrast, middle-SDI regions had the highest number of deaths and DALYs in 2021, whereas low-middle-SDI regions had the highest mortality and DALY rates. Furthermore, low-SDI regions experienced the largest increase in the number of deaths and DALYs. The HSBP-related burden increased with age; in addition, the proportion of deaths or DALYs due to ischaemic heart disease and stroke increased with age, reaching > 75% for those > 25 years of age. The increase in global HSBP-related burden among youth and young adults indicates that current preventative efforts are insufficient. Therefore, targeted measures are needed to counter the trends in HSBP-related diseases and reduce disparities across regions and sexes.
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, TGFβR3 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.
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