The role of necroptosis in atherosclerotic disease.
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ABSTRACT:
SUBMITTER: Leeper NJ
PROVIDER: S-EPMC5419689 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Necroptosis, a distinctive type of programmed cell death different from apoptosis or necrosis, triggered by a series of death receptors such as tumor necrosis factor receptor 1 (TNFR1), TNFR2, and Fas. In case that apoptosis process is blocked, necroptosis pathway is initiated with the activation of three key downstream mediators which are receptor-interacting serine/threonine protein kinase 1 (RIPK1), RIPK3, and mixed lineage kinase domain-like protein (MLKL). The whole process eventually leads to destruction of the cell membrane integrity, swelling of organelles, and severe inflammation. Over the past decade, necroptosis has been found widely involved in life process of human beings and animals. In this review, we attempt to explore the therapeutic prospects of necroptosis regulators by describing its molecular mechanism and the role it played in pathological condition and tissue homeostasis, and to summarize the research and clinical applications of corresponding regulators including small molecule inhibitors, chemicals, Chinese herbal extracts, and biological agents in the treatment of various diseases.
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Project description:Atherosclerotic renovascular disease is a combination of renal artery stenosis and renal ischemia. Blood pressure does not rise until the stenosis is 60% or greater. Disease of both large and small blood vessels is often accompanied by the loss of glomerular filtration rate. Activation of the renin-angiotensin-aldosterone system leads to vasoconstriction and salt retention. Risk factors for atherosclerotic renovascular disease include long-standing hypertension, diabetes, smoking and dyslipidemia. The prevalence of the condition in patients with hypertension resistant to two medications is 20%. As yet, there is no single ideal screening test or evidence-based recommended screening algorithm. Magnetic resonance angiography and computed tomography angiography are noninvasive and have high sensitivity and specificity, but also have high costs associated with them. The captopril renal scan has low sensitivity and specificity in people with renal disease (the population most likely to require the test). Doppler ultrasonography has high sensitivity and specificity in experienced hands, and the renal resistance index, which can easily be added to this test, can identify those with microvascular disease who may not benefit from revascularization. The best determinant of patient outcome is not the degree of renal artery stenosis but the degree of renal parenchymal disease. To date, renal revascularization has not been associated with improved renal survival compared with medical treatment alone. Today, the approach to atherosclerotic renovascular disease is determined by the patient's blood pressure and renal function; possibly, in the future, it will be determined by the result of the renal resistance index as part of a screening algorithm. If the blood pressure is uncontrollable or the renal function is deteriorating, the patient should be considered for renal revascularization initially, with a percutaneous endovascular stent. The management of hypertension involves the use of combinations of antihypertensive agents at doses sufficient to control blood pressure. Medical management also includes aggressive lipid-lowering therapy.
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Project description:The corpus luteum (CL) is a transient endocrine organ, yet molecular mechanisms resulting in its demise are not well known. The presence of phosphorylated mixed lineage kinase domain-like pseudokinase pMLKL(T357/S358) in human and nonhuman primate CL samples (Macaca mulatta and Callithrix jacchus) implied that necroptosis of luteal cells may be involved. In M. mulatta CL, pMLKL positive staining became detectable only from the mid-late luteal phase onwards, pointing to necroptosis during regression of the CL. Cell death, including necroptosis, was previously observed in cultures of human luteal granulosa cells (GCs), an apt model for the study of the human CL. To explore mechanisms of necroptotic cell death in GCs during culture, we performed a proteomic analysis. The levels of 50 proteins were significantly altered after 5 days of culture. Interconnectivity analysis and immunocytochemistry implicated specifically the ceramide salvage pathway to be enhanced. M. mulatta CL transcriptome analysis indicated in vivo relevance. Perturbing endogenous ceramide generation by fumonisin B1 (FB1) and addition of soluble ceramide (C2-CER) yielded opposite actions on viability of GCs and therefore supported the significance of the ceramide pathway. Morphological changes indicated necrotic cell death in the C2-CER treated group. Studies with the pan caspase blocker zVAD-fmk or the necroptosis blocker necrosulfonamid (NSA) further supported that C2-CER induced necroptosis. Our data pinpoint necroptosis in a physiological process, namely CL regression. This raises the possibility that the primate CL could be rescued by pharmacological inhibition of necroptosis or by interaction with ceramide metabolism.
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Project description:Cell death pathways have evolved to maintain tissue homoeostasis and eliminate potentially harmful cells from within an organism, such as cells with damaged DNA that could lead to cancer. Apoptosis, known to eliminate cells in a predominantly non-inflammatory manner, is controlled by two main branches, the intrinsic and extrinsic apoptotic pathways. While the intrinsic pathway is regulated by the Bcl-2 family members, the extrinsic pathway is controlled by the Death receptors, members of the tumour necrosis factor (TNF) receptor superfamily. Death receptors can also activate a pro-inflammatory type of cell death, necroptosis, when Caspase-8 is inhibited. Apoptotic pathways are known to be tightly regulated by post-translational modifications, especially by ubiquitination. This review discusses research on ubiquitination-mediated regulation of apoptotic signalling. Additionally, the emerging importance of ubiquitination in regulating necroptosis is discussed.
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Project description:An age-associated increase in chronic, low-grade sterile inflammation termed "inflammaging" is a characteristic feature of mammalian aging that shows a strong association with occurrence of various age-associated diseases. However, the mechanism(s) responsible for inflammaging and its causal role in aging and age-related diseases are not well understood. Age-associated accumulation of damage-associated molecular patterns (DAMPs) is an important trigger in inflammation and has been proposed as a potential driver of inflammaging. DAMPs can initiate an inflammatory response by binding to the cell surface receptors on innate immune cells. Programmed necrosis, termed necroptosis, is one of the pathways that can release DAMPs, and cell death due to necroptosis is known to induce inflammation. Necroptosis-mediated inflammation plays an important role in a variety of age-related diseases such as Alzheimer's disease, Parkinson's disease, and atherosclerosis. Recently, it was reported that markers of necroptosis increase with age in mice and that dietary restriction, which retards aging and increases lifespan, reduces necroptosis and inflammation. Genetic manipulations that increase lifespan (Ames Dwarf mice) and reduce lifespan (Sod1-/- mice) are associated with reduced and increased necroptosis and inflammation, respectively. While necroptosis evolved to protect cells/tissues from invading pathogens, e.g., viruses, we propose that the age-related increase in oxidative stress, mTOR signaling, and cell senescence results in cells/tissues in old animals being more prone to undergo necroptosis thereby releasing DAMPs, which contribute to the chronic inflammation observed with age. Approach to decrease DAMPs release by reducing/blocking necroptosis is a potentially new approach to reduce inflammaging, retard aging, and improve healthspan.
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Project description:Pancreatic cancer (PC) is the seventh leading cause of cancer-related death. PC incidence has continued to increase by about 1% each year in both men and women. Although the 5-year relative survival rate of PC has increased from 3% to 12%, it is still the lowest among cancers. Hence, novel therapeutic strategies are urgently needed. Challenges in PC-targeted therapeutic strategies stem from the high PC heterogeneity and from the poorly understood interplay between cancer cells and the surrounding microenvironment. Signaling pathways that drive PC cell growth have been the subject of intense scrutiny and interest has been attracted by necroptosis, a distinct type of programmed cell death. In this review, we provide a historical background on necroptosis and a detailed analysis of the ongoing debate on the role of necroptosis in PC malignant progression.
| S-EPMC10454309 | biostudies-literature
Project description:Necroptosis is a form of regulated necrotic cell death that promotes inflammation. In cells undergoing necroptosis, activated RIPK1 kinase mediates the formation of RIPK1/RIPK3/MLKL complex to promote MLKL oligomerization and execution of necroptosis. RIPK1 kinase activity also promotes cell-autonomous activation of proinflammatory cytokine production in necroptosis. However, the signaling pathways downstream of RIPK1 kinase in necroptosis and how RIPK1 kinase activation controls inflammatory response induced by necroptosis are still largely unknown. Here, we quantitatively measured the temporal dynamics of over 7000 confident phosphorylation-sites during necroptosis using mass spectrometry. Our study defined a RIPK1-dependent phosphorylation pattern in late necroptosis that is associated with a proinflammatory component marked by p-S473 TRIM28. We show that the activation of p38 MAPK mediated by oligomerized MLKL promotes the phosphorylation of S473 TRIM28, which in turn mediates inflammation during late necroptosis. Taken together, our study illustrates a mechanism by which p38 MAPK may be activated by oligomerized MLKL to promote inflammation in necroptosis.
| S-EPMC8542044 | biostudies-literature
Project description:Non-alcoholic hepatosteatosis (NASH) due to metabolic syndrome or diabetes mellitus has been identified as the fastest growing cause of hepatocellular carcinoma (HCC), the fourth leading cause of cancer related deaths in the world. Therapeutic options for HCC are limited, and survival after diagnosis is poor (>10%). Thus, a better understanding of the mechanisms that drive the progression of NASH to HCC is critical in developing new strategies to prevent/treat HCC. Chronic inflammation is a key player in the pathogenesis of HCC, however, pathways that drive chronic hepatic inflammation in NASH-driven HCC is not known. Necroptosis is a regulated mode of cell death that causes inflammation and is activated in the livers of patients with NASH. Therefore, we tested whether necroptosis-mediated inflammation plays a role in the progression of NASH to HCC in a mouse model of NASH-induced HCC.
2022-06-30 | GSE200923 | GEO
Project description:CONTEXT:A large body of experimental and observational data has implicated vitamin D deficiency in the development of cardiovascular disease. However, evidence to support routine vitamin D supplementation to prevent or treat cardiovascular disease is lacking. EVIDENCE ACQUISITION:A comprehensive literature review was performed using Pubmed and other literature search engines. EVIDENCE SYNTHESIS:Mounting epidemiological evidence and data from Mendelian randomization studies support a link between vitamin D deficiency and adverse cardiovascular health outcomes, but randomized trial evidence to support vitamin D supplementation is sparse. Current public health guidelines restrict vitamin D intake recommendations to the maintenance of bone health and prevention of fractures. Two recently published large trials (VITAL and ViDA) that assessed the role of moderate-to-high dose vitamin D supplementation as primary prevention for cardiovascular outcomes in the general population had null results, and previous randomized trials have also been generally negative. These findings from general population cohorts that are largely replete in vitamin D may not be applicable to chronic kidney disease (CKD) populations, in which the use of active (1?-hydroxylated) vitamin D compounds is prevalent, or to other high-risk populations. Additionally, recent trials in the CKD population, and trials using vitamin D analogues have been limited. CONCLUSIONS:Current randomized trials of vitamin D supplementation do not support benefits for cardiovascular health, but the evidence remains inconclusive. Additional randomized trials assessing larger numbers of participants with low baseline vitamin D levels, having longer follow-up periods, and testing higher vitamin D dosages, are needed to guide clinical practice.
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Project description:This report describes the change in atherosclerotic renovascular disease (AS-RVD) among hypertensive adults referred for renal duplex sonography (RDS) scan.From Oct 1993 through July 2008, 20,994 patients had RDS at our center. A total of 434 hypertensive patients with two or more RDS exams without intervention comprised the study cohort. Patient demographics (blood pressures, medications, serum creatinine levels, and data from RDS) were collected. Analyses of longitudinal changes in Doppler scan parameters, blood pressures, and renal function were performed by fitting linear growth-curve models. After confirming the linearity of change in Doppler scan parameters among patients with variable number of studies, estimates of mean slopes were calculated using maximum likelihood techniques. For changes in renal function, quadratic growth curves were required to describe longitudinal change.A total of 434 subjects (212 men [49%] and 222 women [51%]; mean age, 64.6 +/- 12.2 years) provided 1351 studies (mean, 3.2 +/- 2.4; range, 2 to 18) for 863 kidneys over a mean follow-up of 34.4 +/- 25.1 months. At baseline, 20.6% of kidneys demonstrated hemodynamically significant stenosis. On follow-up, 72 kidneys (9.1%) demonstrated anatomic progression of disease. A total of 54 kidneys (6.9%) progressed to significant stenosis and 18 (2.3%) progressed to occlusion. Controlling for progression of disease, baseline renal artery status demonstrated a strong association with baseline kidney length (P = .0006). Significant annualized change in renal length was observed (cm change/year +/- standard error of the mean [SEM]: 0.042 +/- 0.011; P = .0002) among both kidneys with and without critical disease at baseline, however, decline in length was significantly greater among kidneys exhibiting progression of renovascular disease (-0.152 +/- 0.028 cm/year; comparison of slopes between groups P = .0005). In the absence of progression, the presence or absence of critical renal artery stenosis at baseline did not affect the rate of decline in renal length. Fitted models for the natural log transform of serum creatinine demonstrated a significant increase during follow-up (P < .0001). No association was observed between change in serum creatinine and baseline renovascular disease status, or its progression.A total of 32% of hypertensive adults referred for RDS demonstrated hemodynamically significant renal artery stenosis. Regardless of the presence or absence of baseline disease, a small percentage of patients demonstrated anatomic progression of AS-RVD. A total of 9.1% demonstrated anatomic progression and 2.3% progressed to occlusion. Although anatomic progression of AS-RVD was associated with an increased rate of decline in renal length, progression did not predict a decline in excretory renal function. Intervention for AS-RVD should be selective and reserved for strict indications.
| S-EPMC2899686 | biostudies-literature