RESUMO
BACKGROUND: Chronic activation of the innate immune system drives inflammation and contributes directly to atherosclerosis. We previously showed that macrophages in the atherogenic plaque undergo RIPK3 (receptor-interacting serine/threonine-protein kinase 3)-MLKL (mixed lineage kinase domain-like protein)-dependent programmed necroptosis in response to sterile ligands such as oxidized low-density lipoprotein and damage-associated molecular patterns and that necroptosis is active in advanced atherosclerotic plaques. Upstream of the RIPK3-MLKL necroptotic machinery lies RIPK1 (receptor-interacting serine/threonine-protein kinase 1), which acts as a master switch that controls whether the cell undergoes NF-κB (nuclear factor κ-light-chain-enhancer of activated B cells)-dependent inflammation, caspase-dependent apoptosis, or necroptosis in response to extracellular stimuli. We therefore set out to investigate the role of RIPK1 in the development of atherosclerosis, which is driven largely by NF-κB-dependent inflammation at early stages. We hypothesize that, unlike RIPK3 and MLKL, RIPK1 primarily drives NF-κB-dependent inflammation in early atherogenic lesions, and knocking down RIPK1 will reduce inflammatory cell activation and protect against the progression of atherosclerosis. METHODS: We examined expression of RIPK1 protein and mRNA in both human and mouse atherosclerotic lesions, and used loss-of-function approaches in vitro in macrophages and endothelial cells to measure inflammatory responses. We administered weekly injections of RIPK1 antisense oligonucleotides to Apoe-/- mice fed a cholesterol-rich (Western) diet for 8 weeks. RESULTS: We find that RIPK1 expression is abundant in early-stage atherosclerotic lesions in both humans and mice. Treatment with RIPK1 antisense oligonucleotides led to a reduction in aortic sinus and en face lesion areas (47.2% or 58.8% decrease relative to control, P<0.01) and plasma inflammatory cytokines (IL-1α [interleukin 1α], IL-17A [interleukin 17A], P<0.05) in comparison with controls. RIPK1 knockdown in macrophages decreased inflammatory genes (NF-κB, TNFα [tumor necrosis factor α], IL-1α) and in vivo lipopolysaccharide- and atherogenic diet-induced NF-κB activation. In endothelial cells, knockdown of RIPK1 prevented NF-κB translocation to the nucleus in response to TNFα, where accordingly there was a reduction in gene expression of IL1B, E-selectin, and monocyte attachment. CONCLUSIONS: We identify RIPK1 as a central driver of inflammation in atherosclerosis by its ability to activate the NF-κB pathway and promote inflammatory cytokine release. Given the high levels of RIPK1 expression in human atherosclerotic lesions, our study suggests RIPK1 as a future therapeutic target to reduce residual inflammation in patients at high risk of coronary artery disease.
Assuntos
Aterosclerose/metabolismo , Inativação Gênica/fisiologia , Mediadores da Inflamação/metabolismo , NF-kappa B/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/biossíntese , Animais , Aterosclerose/genética , Aterosclerose/patologia , Células Cultivadas , Colesterol na Dieta/administração & dosagem , Colesterol na Dieta/efeitos adversos , Feminino , Expressão Gênica , Células Endoteliais da Veia Umbilical Humana , Humanos , Inflamação/genética , Inflamação/metabolismo , Inflamação/patologia , Mediadores da Inflamação/antagonistas & inibidores , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , NF-kappa B/antagonistas & inibidores , NF-kappa B/genética , Proteína Serina-Treonina Quinases de Interação com Receptores/genéticaRESUMO
PURPOSE: Magnetic resonance imaging (MRI) is not beneficial in patients with joint pain and concomitant osteoarthritis (OA). We attempt to determine whether evaluation of OA via X-rays can reduce inappropriate MRI and computed tomography (CT) arthrogram use. In our jurisdiction, CT arthrograms are used as surrogate tests because of MRI wait times. MATERIALS AND METHODS: Our intervention required patients ≥55 years of age scheduled for outpatient MRI of the knee/hip/shoulder at an urban hospital to have X-rays (weight bearing when appropriate) from within 1 year. Red flags (ie, neoplasm, infection) were identified for which MRI would be indicated regardless. Through review of radiographs on picture archiving and communication system/digital media and use of the validated Kellgren-Lawrence (KL) OA scale, radiologists assessed the presence and degree of OA. A finding of significant OA (KL > 2) without red flags would preclude MRI. Monthly averages of MRI and CT arthrogram examinations were measured 33 months before and 23 months following introduction of the intervention. RESULTS: The proportion of protocoled MRI requisitions that were avoided was 21%. If extrapolated to the province of British Columbia, 2419 of 11 700 examinations could have been prevented in the past year. The average monthly number of knee/hip/shoulder MRI examinations as a percentage of total MRI examinations decreased from 4.9% to 4.3% (P < .02) following the intervention. The average monthly number of knee/hip/shoulder CT arthrogram examinations decreased from 20.6 to 12.1 (P < .0001). CONCLUSION: We were able to decrease the number of MRI and CT arthrogram examinations in patients ≥55 years of age with joint pain by implementing an evaluation for OA via recent X-ray imaging.
Assuntos
Artralgia/diagnóstico por imagem , Imageamento por Ressonância Magnética/estatística & dados numéricos , Osteoartrite/diagnóstico por imagem , Idoso , Artrografia , Colúmbia Britânica , Tomada de Decisões , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tomografia Computadorizada por Raios X , Listas de EsperaRESUMO
BACKGROUND AND OBJECTIVE: Palpitations are a common symptom that may indicate cardiac arrhythmias, be a somatic complaint in anxiety disorders, and can be present in patients without either condition. The objective of this review was to explore the pathways and fundamental mechanisms through which individuals appreciate palpitations. OBSERVATIONS: Cardiac afferents provide beat-to-beat sensory information on the heart to the spinal cord, brain stem, and higher brain centers. Cardioception, a subset of interoception ('the physiological sense of the condition of the body'), refers to sensing of the heartbeat. High cardioception is present in persons with lower body mass index, lower percentages of body fat, and anxiety disorders. Low cardioception (lower interoceptive awareness) is associated with psychiatric disorders, such as depression, personality disorders, and schizophrenia. CNS sites associated with heartbeat detection have been identified by functional magnetic resonance imaging studies and heartbeat-evoked electroencephalogram potentials. The right insula, cingulate gyrus, somatomotor and somatosensory cortices nucleus accumbens, left subthalamic nucleus, and left ventral capsule/striatum are implicated in both palpitations and heartbeat detection. Involvement of the brain as a primary modulator of palpitations rests on the data that various areas of the brain are activated in association with cardioception, the ability of focal brain stimulation to induce palpitations, the ability of central alpha receptor agonists and antagonists to modulate palpitations, and suppression of palpitations by transcranial repetitive magnetic stimulation (rTMS). CONCLUSIONS: Palpitations should be viewed as a pathway extending from the heart to the brain. Palpitations are, in part, a reflection of an individual's cardioception awareness, which is modulated by body size, percentage of body fat, and psychological or psychiatric conditions. Palpitations can originate in the brain and involve central neurotransmitters. Treatment of palpitations unrelated to cardiac arrhythmias or anxiety disorders should consider the use of central alpha-2 agonists and possibly rTMS.
Assuntos
Interocepção , Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/etiologia , Encéfalo , Frequência Cardíaca , Humanos , Interocepção/fisiologia , Imageamento por Ressonância MagnéticaRESUMO
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
RESUMO
Obesity is a major public health burden worldwide and is characterized by chronic low-grade inflammation driven by the cooperation of the innate immune system and dysregulated metabolism in adipose tissue and other metabolic organs. Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) is a central regulator of inflammatory cell function that coordinates inflammation, apoptosis and necroptosis in response to inflammatory stimuli. Here we show that genetic polymorphisms near the human RIPK1 locus associate with increased RIPK1 gene expression and obesity. We show that one of these single nucleotide polymorphisms is within a binding site for E4BP4 and increases RIPK1 promoter activity and RIPK1 gene expression in adipose tissue. Therapeutic silencing of RIPK1 in vivo in a mouse model of diet-induced obesity dramatically reduces fat mass, total body weight and improves insulin sensitivity, while simultaneously reducing macrophage and promoting invariant natural killer T cell accumulation in adipose tissue. These findings demonstrate that RIPK1 is genetically associated with obesity, and reducing RIPK1 expression is a potential therapeutic approach to target obesity and related diseases.