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1.
Artigo em Inglês | MEDLINE | ID: mdl-34619105

RESUMO

Up to 50% of the people who have died from COVID-19 had metabolic and vascular disorders. Notably, there are many direct links between COVID-19 and the metabolic and endocrine systems. Thus, not only are patients with metabolic dysfunction (eg, obesity, hypertension, non-alcoholic fatty liver disease, and diabetes) at an increased risk of developing severe COVID-19 but also infection with SARS-CoV-2 might lead to new-onset diabetes or aggravation of pre-existing metabolic disorders. In this Review, we provide an update on the mechanisms of how metabolic and endocrine disorders might predispose patients to develop severe COVID-19. Additionally, we update the practical recommendations and management of patients with COVID-19 and post-pandemic. Furthermore, we summarise new treatment options for patients with both COVID-19 and diabetes, and highlight current challenges in clinical management.

2.
Nat Commun ; 12(1): 5078, 2021 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-34426578

RESUMO

Genome-wide association studies (GWAS) have identified loci for kidney disease, but the causal variants, genes, and pathways remain unknown. Here we identify two kidney disease genes Dipeptidase 1 (DPEP1) and Charged Multivesicular Body Protein 1 A (CHMP1A) via the triangulation of kidney function GWAS, human kidney expression, and methylation quantitative trait loci. Using single-cell chromatin accessibility and genome editing, we fine map the region that controls the expression of both genes. Mouse genetic models demonstrate the causal roles of both genes in kidney disease. Cellular studies indicate that both Dpep1 and Chmp1a are important regulators of a single pathway, ferroptosis and lead to kidney disease development via altering cellular iron trafficking.


Assuntos
Dipeptidases/genética , Ferroptose/genética , Loci Gênicos , Predisposição Genética para Doença , Nefropatias/genética , Proteínas de Transporte Vesicular/genética , Animais , Nitrogênio da Ureia Sanguínea , Cromatina/metabolismo , Cisplatino , Metilação de DNA/genética , Dipeptidases/deficiência , Dipeptidases/metabolismo , Ácido Fólico , Edição de Genes , Regulação da Expressão Gênica , Estudo de Associação Genômica Ampla , Haploinsuficiência/genética , Humanos , Ferro/metabolismo , Rim/patologia , Nefropatias/induzido quimicamente , Camundongos , Necroptose/genética , Especificidade de Órgãos , Mapeamento Físico do Cromossomo , Piroptose/genética , Locos de Características Quantitativas , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas de Transporte Vesicular/deficiência , Proteínas de Transporte Vesicular/metabolismo
3.
Nat Commun ; 12(1): 4402, 2021 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-34285231

RESUMO

Acute kidney injury (AKI) is morphologically characterized by a synchronized plasma membrane rupture of cells in a specific section of a nephron, referred to as acute tubular necrosis (ATN). Whereas the involvement of necroptosis is well characterized, genetic evidence supporting the contribution of ferroptosis is lacking. Here, we demonstrate that the loss of ferroptosis suppressor protein 1 (Fsp1) or the targeted manipulation of the active center of the selenoprotein glutathione peroxidase 4 (Gpx4cys/-) sensitize kidneys to tubular ferroptosis, resulting in a unique morphological pattern of tubular necrosis. Given the unmet medical need to clinically inhibit AKI, we generated a combined small molecule inhibitor (Nec-1f) that simultaneously targets receptor interacting protein kinase 1 (RIPK1) and ferroptosis in cell lines, in freshly isolated primary kidney tubules and in mouse models of cardiac transplantation and of AKI and improved survival in models of ischemia-reperfusion injury. Based on genetic and pharmacological evidence, we conclude that GPX4 dysfunction hypersensitizes mice to ATN during AKI. Additionally, we introduce Nec-1f, a solid inhibitor of RIPK1 and weak inhibitor of ferroptosis.


Assuntos
Injúria Renal Aguda/patologia , Ferroptose/fisiologia , Túbulos Renais/patologia , Traumatismo por Reperfusão/patologia , Injúria Renal Aguda/tratamento farmacológico , Injúria Renal Aguda/etiologia , Animais , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Cisplatino/administração & dosagem , Cisplatino/toxicidade , Modelos Animais de Doenças , Células Epiteliais , Feminino , Ferroptose/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Células HT29 , Transplante de Coração/efeitos adversos , Humanos , Imidazóis/química , Imidazóis/farmacologia , Imidazóis/uso terapêutico , Indóis/química , Indóis/farmacologia , Indóis/uso terapêutico , Masculino , Camundongos , Camundongos Transgênicos , Microssomos Hepáticos , Proteínas Mitocondriais/metabolismo , Células NIH 3T3 , Necrose/tratamento farmacológico , Necrose/etiologia , Necrose/patologia , Oxirredutases/genética , Oxirredutases/metabolismo , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/antagonistas & inibidores , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Cultura Primária de Células , Proteína Serina-Treonina Quinases de Interação com Receptores/antagonistas & inibidores , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/etiologia
4.
Nat Rev Endocrinol ; 17(8): 497-510, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34135504

RESUMO

The death of endocrine cells is involved in type 1 diabetes mellitus, autoimmunity, adrenopause and hypogonadotropism. Insights from research on basic cell death have revealed that most pathophysiologically important cell death is necrotic in nature, whereas regular metabolism is maintained by apoptosis programmes. Necrosis is defined as cell death by plasma membrane rupture, which allows the release of damage-associated molecular patterns that trigger an immune response referred to as necroinflammation. Regulated necrosis comes in different forms, such as necroptosis, pyroptosis and ferroptosis. In this Perspective, with a focus on the endocrine environment, we introduce these cell death pathways and discuss the specific consequences of regulated necrosis. Given that clinical trials of necrostatins for the treatment of autoimmune conditions have already been initiated, we highlight the therapeutic potential of such novel therapeutic approaches that, in our opinion, should be tested in endocrine disorders in the future.


Assuntos
Doenças do Sistema Endócrino/etiologia , Necrose/fisiopatologia , Animais , Apoptose/fisiologia , Morte Celular/fisiologia , Doenças do Sistema Endócrino/patologia , Doenças do Sistema Endócrino/fisiopatologia , Doenças do Sistema Endócrino/terapia , Humanos , Transdução de Sinais/fisiologia , Terapias em Estudo/métodos , Terapias em Estudo/tendências
5.
Nat Commun ; 12(1): 3534, 2021 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-34112801

RESUMO

Metabolic diseases are associated with an increased risk of severe COVID-19 and conversely, new-onset hyperglycemia and complications of preexisting diabetes have been observed in COVID-19 patients. Here, we performed a comprehensive analysis of pancreatic autopsy tissue from COVID-19 patients using immunofluorescence, immunohistochemistry, RNA scope and electron microscopy and detected SARS-CoV-2 viral infiltration of beta-cells in all patients. Using SARS-CoV-2 pseudoviruses, we confirmed that isolated human islet cells are permissive to infection. In eleven COVID-19 patients, we examined the expression of ACE2, TMPRSS and other receptors and factors, such as DPP4, HMBG1 and NRP1, that might facilitate virus entry. Whereas 70% of the COVID-19 patients expressed ACE2 in the vasculature, only 30% displayed ACE2-expression in beta-cells. Even in the absence of manifest new-onset diabetes, necroptotic cell death, immune cell infiltration and SARS-CoV-2 viral infection of pancreatic beta-cells may contribute to varying degrees of metabolic dysregulation in patients with COVID-19.


Assuntos
Enzima de Conversão de Angiotensina 2/metabolismo , COVID-19/patologia , Células Secretoras de Insulina/virologia , Receptores de Coronavírus/metabolismo , SARS-CoV-2/isolamento & purificação , Serina Endopeptidases/metabolismo , Adulto , Idoso , Autopsia , Complicações do Diabetes/patologia , Complicações do Diabetes/virologia , Diabetes Mellitus/patologia , Dipeptidil Peptidase 4/metabolismo , Feminino , Proteínas HMGN/metabolismo , Humanos , Células Secretoras de Insulina/metabolismo , Masculino , Pessoa de Meia-Idade , Neuropilina-1/metabolismo , Especificidade de Órgãos/fisiologia
6.
Elife ; 102021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33646117

RESUMO

Interleukin-4-induced-1 (IL4i1) is an amino acid oxidase secreted from immune cells. Recent observations have suggested that IL4i1 is pro-tumorigenic via unknown mechanisms. As IL4i1 has homologs in snake venoms (L-amino acid oxidases [LAAO]), we used comparative approaches to gain insight into the mechanistic basis of how conserved amino acid oxidases regulate cell fate and function. Using mammalian expressed recombinant proteins, we found that venom LAAO kills cells via hydrogen peroxide generation. By contrast, mammalian IL4i1 is non-cytotoxic and instead elicits a cell protective gene expression program inhibiting ferroptotic redox death by generating indole-3-pyruvate (I3P) from tryptophan. I3P suppresses ferroptosis by direct free radical scavenging and through the activation of an anti-oxidative gene expression program. Thus, the pro-tumor effects of IL4i1 are likely mediated by local anti-ferroptotic pathways via aromatic amino acid metabolism, arguing that an IL4i1 inhibitor may modulate tumor cell death pathways.

8.
Cell Death Differ ; 28(2): 748-763, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32929218

RESUMO

The non-canonical inflammasome is an emerging crucial player in the development of inflammatory and neurodegenerative diseases. It is activated by direct sensing of cytosolic lipopolysaccharide (LPS) by caspase-11 (CASP11), which then induces pyroptosis, an inflammatory form of regulated cell death. Here, we report that tyrosine kinase 2 (TYK2), a cytokine receptor-associated kinase, is a critical upstream regulator of CASP11. Absence of TYK2 or its kinase activity impairs the transcriptional induction of CASP11 in vitro and in vivo and protects mice from LPS-induced lethality. Lack of TYK2 or its enzymatic activity inhibits macrophage pyroptosis and impairs release of mature IL-1ß and IL-18 specifically in response to intracellular LPS. Deletion of TYK2 in myeloid cells reduces LPS-induced IL-1ß and IL-18 production in vivo, highlighting the importance of these cells in the inflammatory response to LPS. In support of our data generated with genetically engineered mice, pharmacological inhibition of TYK2 reduced LPS-induced upregulation of CASP11 in bone marrow-derived macrophages (BMDMs) and of its homolog CASP5 in human macrophages. Our study provides insights into the regulation of CASP11 in vivo and uncovered a novel link between TYK2 activity and CASP11-dependent inflammation.

9.
Gut ; 70(3): 485-498, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32503845

RESUMO

OBJECTIVE: The intestinal epithelium is a rapidly renewing tissue which plays central roles in nutrient uptake, barrier function and the prevention of intestinal inflammation. Control of epithelial differentiation is essential to these processes and is dependent on cell type-specific activity of transcription factors which bind to accessible chromatin. Here, we studied the role of SET Domain Bifurcated Histone Lysine Methyltransferase 1, also known as ESET (SETDB1), a histone H3K9 methyltransferase, in intestinal epithelial homeostasis and IBD. DESIGN: We investigated mice with constitutive and inducible intestinal epithelial deletion of Setdb1, studied the expression of SETDB1 in patients with IBD and mouse models of IBD, and investigated the abundance of SETDB1 variants in healthy individuals and patients with IBD. RESULTS: Deletion of intestinal epithelial Setdb1 in mice was associated with defects in intestinal epithelial differentiation, barrier disruption, inflammation and mortality. Mechanistic studies showed that loss of SETDB1 leads to de-silencing of endogenous retroviruses, DNA damage and intestinal epithelial cell death. Predicted loss-of-function variants in human SETDB1 were considerably less frequently observed than expected, consistent with a critical role of SETDB1 in human biology. While the vast majority of patients with IBD showed unimpaired mucosal SETDB1 expression, comparison of IBD and non-IBD exomes revealed over-representation of individual rare missense variants in SETDB1 in IBD, some of which are predicted to be associated with loss of function and may contribute to the pathogenesis of intestinal inflammation. CONCLUSION: SETDB1 plays an essential role in intestinal epithelial homeostasis. Future work is required to investigate whether rare variants in SETDB1 contribute to the pathogenesis of IBD.

10.
Sci Adv ; 6(47)2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33208362

RESUMO

Gasdermin D (GSDMD) is a pore-forming protein that promotes pyroptosis and release of proinflammatory cytokines. Recent studies revealed that apoptotic caspase-8 directly cleaves GSDMD to trigger pyroptosis. However, the molecular requirements for caspase-8-dependent GSDMD cleavage and the physiological impact of this signaling axis are unresolved. Here, we report that caspase-8-dependent GSDMD cleavage confers susceptibility to tumor necrosis factor (TNF)-induced lethality independently of caspase-1 and that GSDMD activation provides host defense against Yersinia infection. We further demonstrate that GSDMD inactivation by apoptotic caspases at aspartate 88 (D88) suppresses TNF-induced lethality but promotes anti-Yersinia defense. Last, we show that caspase-8 dimerization and autoprocessing are required for GSDMD cleavage, and provide evidence that the caspase-8 autoprocessing and activity on various complexes correlate with its ability to directly cleave GSDMD. These findings reveal GSDMD as a potential therapeutic target to reduce inflammation associated with mutations in the death receptor signaling machinery.

11.
Artigo em Inglês | MEDLINE | ID: mdl-32691160

RESUMO

The juxtaglomerular renin-producing cells (RPC) of the kidney are referred to as the major source of circulating renin. Renin is the limiting factor in renin-angiotensin system (RAS), which represents a proteolytic cascade in blood plasma that plays a central role in the regulation of blood pressure. Further cells disseminated in the entire organism express renin at a low level as part of tissue RASs, which are thought to locally modulate the effects of systemic RAS. In recent years, it became increasingly clear that the renal RPC are involved in developmental, physiological, and pathophysiological processes outside RAS. Based on recent experimental evidence, a novel concept emerges postulating that next to their traditional role, the RPC have non-canonical RAS-independent progenitor and renoprotective functions. Moreover, the RPC are part of a widespread renin lineage population, which may act as a global stem cell pool coordinating homeostatic, stress, and regenerative responses throughout the organism. This review focuses on the RAS-unrelated functions of RPC - a dynamic research area that increasingly attracts attention.


Assuntos
Rim/citologia , Sistema Renina-Angiotensina , Renina , Pressão Sanguínea , Humanos , Rim/metabolismo , Renina/metabolismo , Células-Tronco/metabolismo
13.
Circ Res ; 127(4): 486-501, 2020 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-32349646

RESUMO

RATIONALE: Maintaining iron homeostasis is essential for proper cardiac function. Both iron deficiency and iron overload are associated with cardiomyopathy and heart failure via complex mechanisms. Although ferritin plays a central role in iron metabolism by storing excess cellular iron, the molecular function of ferritin in cardiomyocytes remains unknown. OBJECTIVE: To characterize the functional role of Fth (ferritin H) in mediating cardiac iron homeostasis and heart disease. METHODS AND RESULTS: Mice expressing a conditional Fth knockout allele were crossed with 2 distinct Cre recombinase-expressing mouse lines, resulting in offspring that lack Fth expression specifically in myocytes (MCK-Cre) or cardiomyocytes (Myh6-Cre). Mice lacking Fth in cardiomyocytes had decreased cardiac iron levels and increased oxidative stress, resulting in mild cardiac injury upon aging. However, feeding these mice a high-iron diet caused severe cardiac injury and hypertrophic cardiomyopathy, with molecular features typical of ferroptosis, including reduced glutathione (GSH) levels and increased lipid peroxidation. Ferrostatin-1, a specific inhibitor of ferroptosis, rescued this phenotype, supporting the notion that ferroptosis plays a pathophysiological role in the heart. Finally, we found that Fth-deficient cardiomyocytes have reduced expression of the ferroptosis regulator Slc7a11, and overexpressing Slc7a11 selectively in cardiomyocytes increased GSH levels and prevented cardiac ferroptosis. CONCLUSIONS: Our findings provide compelling evidence that ferritin plays a major role in protecting against cardiac ferroptosis and subsequent heart failure, thereby providing a possible new therapeutic target for patients at risk of developing cardiomyopathy.


Assuntos
Sistema y+ de Transporte de Aminoácidos/metabolismo , Apoferritinas/deficiência , Cardiomiopatias/etiologia , Ferroptose/fisiologia , Ferro/metabolismo , Miocárdio/metabolismo , Envelhecimento , Alelos , Animais , Apoferritinas/efeitos adversos , Apoferritinas/genética , Cardiomiopatias/metabolismo , Cardiomiopatias/prevenção & controle , Cardiomiopatia Hipertrófica/etiologia , Cardiomiopatia Hipertrófica/prevenção & controle , Cruzamentos Genéticos , Cicloexilaminas/administração & dosagem , Glutationa/metabolismo , Insuficiência Cardíaca/etiologia , Homeostase , Hipertrofia Ventricular Esquerda/etiologia , Ferro/deficiência , Sobrecarga de Ferro , Ferro na Dieta/efeitos adversos , Peroxidação de Lipídeos , Masculino , Camundongos , Camundongos Transgênicos , Miócitos Cardíacos/metabolismo , Estresse Oxidativo , Fenilenodiaminas/administração & dosagem , Espécies Reativas de Oxigênio/metabolismo
15.
Cell Chem Biol ; 27(4): 448-462, 2020 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-32302582

RESUMO

In the last decade, the role of apoptosis in the pathophysiology of acute kidney injury (AKI) and AKI to chronic kidney disease (CKD) progression has been revisited as our understanding of ferroptosis and necroptosis has emerged. A growing body of evidence, reviewed here, ascribes a central pathophysiological role for ferroptosis and necroptosis to AKI, nephron loss, and acute tubular necrosis. We will introduce concepts to the non-cell-autonomous manner of kidney tubular injury during ferroptosis, a phenomenon that we refer to as a "wave of death." We hypothesize that necroptosis might initiate cell death propagation through ferroptosis. The remaining necrotic debris requires effective removal processes to prevent a secondary inflammatory response, referred to as necroinflammation. Open questions include the differences in the immunogenicity of ferroptosis and necroptosis, and the specificity of necrostatins and ferrostatins to therapeutically target these processes to prevent AKI-to-CKD progression and end-stage renal disease.


Assuntos
Injúria Renal Aguda/patologia , Ferroptose , Necroptose , Insuficiência Renal Crônica/patologia , Injúria Renal Aguda/metabolismo , Proteínas Relacionadas à Autofagia/metabolismo , Humanos , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Insuficiência Renal Crônica/metabolismo , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Síndrome do Desconforto Respiratório/metabolismo , Síndrome do Desconforto Respiratório/patologia , Transdução de Sinais
17.
Dev Cell ; 51(5): 548-549, 2019 12 02.
Artigo em Inglês | MEDLINE | ID: mdl-31794716

RESUMO

Ferroptosis causes clinically relevant amounts of necrosis during the course of heart attacks and acute kidney injury. However, ferroptosis is still a very young research field. In this issue of Developmental Cell, Brown et al. describe the pentaspan membrane glycoprotein prominin-2 as a novel endogenous ferroptosis inhibitor.


Assuntos
Ferroptose , Ferro , Antígeno AC133 , Humanos , Glicoproteínas de Membrana , Necrose
18.
Proc Natl Acad Sci U S A ; 116(44): 22269-22274, 2019 10 29.
Artigo em Inglês | MEDLINE | ID: mdl-31611400

RESUMO

Adrenocortical carcinomas (ACCs) are rare and highly malignant cancers associated with poor survival of patients. Currently, mitotane, a nonspecific derivative of the pesticide DDT (1,1-(dichlorobiphenyl)-2,2-dichloroethane), is used as the standard treatment, but its mechanism of action in ACCs remains elusive. Here we demonstrate that the human ACC NCI-H295R cell line is remarkably sensitive to induction of ferroptosis, while mitotane does not induce this iron-dependent mode of regulated necrosis. Supplementation with insulin, transferrin, and selenium (ITS) is commonly used to keep NCI-H295R cells in cell culture. We show that this supplementation prevents spontaneous ferroptosis, especially when it contains polyunsaturated fatty acids (PUFAs), such as linoleic acid. Inhibitors of apoptosis (zVAD, emricasan) do not prevent the mitotane-induced cell death but morphologically prevent membrane blebbing. The expression of glutathione peroxidase 4 (GPX4) in H295R cells, however, is significantly higher when compared to HT1080 fibrosarcoma cells, suggesting a role for ferroptosis. Direct inhibition of GPX4 in H295R cells led to high necrotic populations compared to control, while cotreatment with ferrostatin-1 (Fer-1) completely reverted ferroptosis. Interestingly, the analysis of public databases revealed that several key players of the ferroptosis pathway are hypermethylated and/or mutated in human ACCs. Finally, we also detected that growth hormone-releasing hormone (GHRH) antagonists, such as MIA602, kill H295R cells in a nonapoptotic manner. In summary, we found elevated expression of GPX4 and higher sensitivity to ferroptosis in ACCs. We hypothesize that instead of treatment with mitotane, human adrenocortical carcinomas may be much more sensitive to induction of ferroptosis.


Assuntos
Neoplasias do Córtex Suprarrenal/metabolismo , Carcinoma Adrenocortical/metabolismo , Ferroptose/efeitos dos fármacos , Células 3T3 , Animais , Apoptose/efeitos dos fármacos , Células HEK293 , Células HT29 , Humanos , Insulina/metabolismo , Ferro/metabolismo , Ácido Linoleico/metabolismo , Camundongos , Mitotano/toxicidade , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/genética , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Selênio/metabolismo , Sermorelina/análogos & derivados , Sermorelina/farmacologia , Transferrina/metabolismo
19.
Kidney Int ; 96(5): 1061-1063, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31648694

RESUMO

Cell death is a pathophysiological component of acute tubular necrosis and acute kidney injury. Regulated necrosis, however, comes in several different forms. Although necroptosis and ferroptosis have been recently characterized in acute kidney injury, pyroptosis has not been assessed in detail. In this issue of Kidney International, Miao and Yin et al. investigate the role of gasdermin D, a protein that can form plasma membrane pores.


Assuntos
Injúria Renal Aguda , Piroptose , Caspases , Células Epiteliais , Humanos , Interleucina-18
20.
Physiol Rev ; 99(4): 1765-1817, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31364924

RESUMO

Twelve regulated cell death programs have been described. We review in detail the basic biology of nine including death receptor-mediated apoptosis, death receptor-mediated necrosis (necroptosis), mitochondrial-mediated apoptosis, mitochondrial-mediated necrosis, autophagy-dependent cell death, ferroptosis, pyroptosis, parthanatos, and immunogenic cell death. This is followed by a dissection of the roles of these cell death programs in the major cardiac syndromes: myocardial infarction and heart failure. The most important conclusion relevant to heart disease is that regulated forms of cardiomyocyte death play important roles in both myocardial infarction with reperfusion (ischemia/reperfusion) and heart failure. While a role for apoptosis in ischemia/reperfusion cannot be excluded, regulated forms of necrosis, through both death receptor and mitochondrial pathways, are critical. Ferroptosis and parthanatos are also likely important in ischemia/reperfusion, although it is unclear if these entities are functioning as independent death programs or as amplification mechanisms for necrotic cell death. Pyroptosis may also contribute to ischemia/reperfusion injury, but potentially through effects in non-cardiomyocytes. Cardiomyocyte loss through apoptosis and necrosis is also an important component in the pathogenesis of heart failure and is mediated by both death receptor and mitochondrial signaling. Roles for immunogenic cell death in cardiac disease remain to be defined but merit study in this era of immune checkpoint cancer therapy. Biology-based approaches to inhibit cell death in the various cardiac syndromes are also discussed.


Assuntos
Morte Celular , Citotoxicidade Imunológica , Cardiopatias/patologia , Mitocôndrias Cardíacas/patologia , Miocárdio/patologia , Animais , Apoptose , Proteínas Reguladoras de Apoptose/metabolismo , Autofagia , Proteínas Relacionadas à Autofagia/metabolismo , Cardiopatias/imunologia , Cardiopatias/metabolismo , Cardiopatias/fisiopatologia , Humanos , Mitocôndrias Cardíacas/imunologia , Mitocôndrias Cardíacas/metabolismo , Miocárdio/imunologia , Miocárdio/metabolismo , Necrose , Piroptose , Transdução de Sinais
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