Cross-Talk of NADPH Oxidases and Inflammation in Obesity

Obesity is a major risk factor for cardiovascular and metabolic diseases. Multiple experimental and clinical studies have shown increased oxidative stress and inflammation linked to obesity. NADPH oxidases are major sources of reactive oxygen species in the cardiovascular system and in metabolically active cells and organs. An impaired balance due to the increased formation of reactive oxygen species and a reduced antioxidative capacity contributes to the pathophysiology of cardiovascular and metabolic diseases and is linked to inflammation as a major pathomechanism in cardiometabolic diseases. Non-alcoholic fatty liver disease is particularly characterized by increased oxidative stress and inflammation. In recent years, COVID-19 infections have also increased oxidative stress and inflammation in infected cells and tissues. Increasing evidence supports the idea of an increased risk for severe clinical complications of cardiometabolic diseases after COVID-19. In this review, we discuss the role of oxidative stress and inflammation in experimental models and clinical studies of obesity, cardiovascular diseases, COVID-19 infections and potential therapeutic strategies

Peritoneal VEGF-A expression is regulated by TGF-β1 through an ID1 pathway in women with endometriosis

VEGF-A, an angiogenic factor, is increased in the peritoneal fluid of women with endometriosis. The cytokine TGF-β1 is thought to play a role in the establishment of endometriosis lesions. Inhibitor of DNA binding (ID) proteins are transcriptional targets of TGF-β1 and ID1 has been implicated in VEGF-A regulation during tumor angiogenesis. Herein, we determined whether peritoneal expression of VEGF-A is regulated by TGF-β1 through the ID1 pathway in women with endometriosis. VEGF-A was measured in peritoneal fluid by ELISA (n = 16). VEGF-A and ID1 expression was examined in peritoneal biopsies (n = 13), and primary peritoneal and immortalized mesothelial cells (MeT5A) by immunohistochemistry, qRT-PCR and ELISA. VEGF-A was increased in peritoneal fluid from women with endometriosis and levels correlated with TGF-β1 concentrations (P < 0.05). VEGF-A was immunolocalized to peritoneal mesothelium and TGF-β1 increased VEGFA mRNA (P < 0.05) and protein (P < 0.05) in mesothelial cells. ID1 was increased in peritoneum from women with endometriosis and TGF-β1 increased concentrations of ID1 mRNA (P < 0.05) in mesothelial cells. VEGF-A regulation through ID1 was confirmed by siRNA in MeT5A cells (P < 0.05). Our data supports role for ID1 in the pathophysiology of endometriosis, as an effector of TGFβ1 dependent upregulation of VEGF-A, and highlights a novel potential therapeutic target

Advancing research on regulatory autoantibodies targeting GPCRs: insights from the 5th international symposium

The 5th International Symposium on Regulatory Autoantibodies Targeting GPCR (RAB-GPCRs) advanced the understanding of the significant role played by autoantibodies targeting G-protein-coupled receptors (GPCRs) in various human diseases. Once considered passive markers, RAB-GPCRs are now recognized as active modulators of cellular signaling, immune regulation, and inflammation. The symposium highlighted their involvement in multiple prominent pathologies, including autoimmune diseases, cardio- and cerebrovascular diseases, and neuroimmunologic disorders such as myalgic encephalomyelitis/chronic fatigue syndrome and post-COVID-19 syndrome (ME/CFS/PCS), as well as solid organ and hematopoietic stem cell transplantation (SOT/HSCT). Experts from rheumatology, immunology, and neurology presented interdisciplinary discussions on the potential of RAB-GPCRs as biomarkers and therapeutic targets. Advances in screening methods, biomarker identification, and therapeutic strategies were shared, emphasizing their diagnostic potential and application in novel therapeutic interventions. This report summarizes key insights from the symposium, particularly focusing on the modulatory properties of RAB-GPCRs and their relevance in both immune-mediated diseases and other pathologies (e.g., vascular, degenerative) that are traditionally not considered primarily immune-mediated. Ongoing research is expected to further establish these autoantibodies as crucial components in disease modulation and systems biology contexts, offering new opportunities for precision medicine and improved clinical outcomes in immune-related disorders

Optimum design of steel bridges including corrosion effect using TLBO

This study presents optimum design of plane steel bridges considering corrosion effect by using teaching-learning based optimization (TLBO) method. Optimum solutions of three different bridge problems are linearly carried out including and excluding corrosion effect. The member cross sections are selected from a pre-specified list of 128 W profiles taken from American Institute of Steel Construction (AISC). A computer program is coded in MATLAB to carry out optimum design interacting with SAP2000 using OAPI (Open Application Programming Interface). The stress constraints are incorporated as indicated in AISC Allowable Stress Design (ASD) specifications and also displacement constraints are applied in optimum design. The results obtained from analysis show that the corrosion effect on steel profile surfaces causes a crucial increase on the minimum steel weight of bridges. Moreover, the results show that the method proposed is applicable and robust to reach the destination even for complex problems. Copyright © 2017 Techno-Press, Ltd

POS0474 ACTIVATION AND HYPERSENSITIZATION OF THE ANGIOTENSIN II TYPE 1 AND ENDOTHELIN-1 TYPE A RECEPTORS BY AGONISTIC AUTOANTIBODIES CONTRIBUTES TO VASCULAR INJURY IN SCLERODERMA RENAL CRISIS

BackgroundScleroderma renal crisis (SRC) is a vascular complication of systemic sclerosis (SSc) with substantial risks for end-stage renal disease and death. Activating autoantibodies (Abs) targeting the angiotensin II type 1 (AT1R) and the endothelin-1 type A receptor (ETAR) are suggested to contribute to the vasculopathy in SSc (1, 2).ObjectivesHere, we sought to determine their pathogenic significance for acute renal vascular injury.MethodsIgG from patients with SRC was studied for AT1R and ETAR dependent biologic effects on isolated rat renal interlobar arteries and vascular cells including contraction, signaling, and mechanisms of receptor activation. A cohort of ten patients with refractory SRC received multimodal treatment including AT1R and ETAR inhibition and plasma exchange and was followed for improvement of kidney function.ResultsIn myography experiments, patient IgG exerted vasoconstriction (mean 6.5% of KCl induced contraction [95% confidence interval (95 CI) 5.0-8.1]) whereas control IgG did not (0.6% [95 CI 0.3-1.0]). The response was sensitive to inhibition of AT1R (3.0% [95% CI 1.4-4.7]) and ETAR (1.0% [95 CI 0.6-1.3]) and relied on MEK-ERK signaling. Contraction induced by angiotensin II and endothelin-1 was amplified by anti-AT1R and anti-ETAR Abs with substantial crosstalk between both receptors implicating autoimmune receptor hypersensitization. Co-immunoprecipitation experiments indicated heterodimerization between both receptor types enabling functional interrelation by structural interactions. 30% of patients with refractory SRC had improved kidney function after multimodal therapy.ConclusionWe provide experimental and clinical evidence that agonistic Abs may contribute to SRC. Novel therapies targeted at autoimmune hyperactivation of AT1R and ETAR might improve outcomes in severe cases of SRC.References[1]Riemekasten, G. et al. Involvement of functional autoantibodies against vascular receptors in systemic sclerosis. Ann. Rheum. Dis. 70, 530–536 (2011).[2]Becker, M. O. et al. Vascular receptor autoantibodies in pulmonary arterial hypertension associated with systemic sclerosis. Am. J. Respir. Crit. Care Med. 190, 808–817 (2014).Figure 1.Contraction of isolated rat renal interlobar arteries in response to IgG isolated from patients with scleroderma renal crisis (SRC) is dependent on angiotensin II typ 1 (AT1R) and endothelin-1 type A receptors (ETAR). Small vessel myography of artery rings exposed to (a) different concentrations of IgG isolated from healthy controls (Control IgG) or patients with SRC (SRC IgG). n = 12. *P&lt;0.001 for SRC IgG versus Control IgG, #P&lt;0.01 for 1.0 mg/mL versus 0.25 mg/mL and P&lt;0.05 for 1.0 mg/mL versus 0.5 mg/mL. (b) Myography of vessels exposed to 1.0 mg/mL Control IgG or SRC IgG after pretreatment with an AT1R blocker (AT1RB, valsartan), an ETAR blocker (ETARB, sitaxsentan) or a dual endothelin-1 type A and type B receptor blocker (ETA/BRB, bosentan). n = 12. **P&lt;0.01, ***P&lt;0.001. Contraction is expressed as % of the maximal contraction in response to 60 mM KCl of each individual vessel. Mean±SEM.Figure 2.Interdependence of the angiotensin II (AngII) type 1 receptor (AT1R) and endothelin-1 (ET-1) receptors (ETA/BR) in the contractile response of isolated rat renal interlobar arteries to AngII and ET-1 in the presence of anti- AT1R and anti-ETAR activating autoantibodies.Small vessel myography of artery rings exposed to 1.0 mg/mL IgG isolated from healthy controls (Control IgG) or patients with scleroderma renal crisis (SRC IgG) and natural ligands with and without pretreatment with receptor blockers as indicated. (a) Additional stimulation with 1000 nM AngII ± ETA/BR blocker (ETA/BRB) bosentan. n = 11-18. (b) Additional stimulation with 100 nM ET-1 ± AT1R blocker (AT1RB) valsartan. n = 6-12. Contraction is expressed as % of the maximal contraction in response to 60 mM KCl of each individual vessel. Mean±SEM. **P&lt;0.01, ***P&lt;0.001.Disclosure of InterestsNone declared.</jats:sec

Cross-Talk of NADPH Oxidases and Inflammation in Obesity

Obesity is a major risk factor for cardiovascular and metabolic diseases. Multiple experimental and clinical studies have shown increased oxidative stress and inflammation linked to obesity. NADPH oxidases are major sources of reactive oxygen species in the cardiovascular system and in metabolically active cells and organs. An impaired balance due to the increased formation of reactive oxygen species and a reduced antioxidative capacity contributes to the pathophysiology of cardiovascular and metabolic diseases and is linked to inflammation as a major pathomechanism in cardiometabolic diseases. Non-alcoholic fatty liver disease is particularly characterized by increased oxidative stress and inflammation. In recent years, COVID-19 infections have also increased oxidative stress and inflammation in infected cells and tissues. Increasing evidence supports the idea of an increased risk for severe clinical complications of cardiometabolic diseases after COVID-19. In this review, we discuss the role of oxidative stress and inflammation in experimental models and clinical studies of obesity, cardiovascular diseases, COVID-19 infections and potential therapeutic strategies

Sex-specific mTOR signaling determines sexual dimorphism in myocardial adaptation in normotensive DOCA-salt model

The deoxycorticosterone acetate (DOCA)-salt mouse model exhibits adverse cardiac remodeling in male mice and cardiac protection in female mice, even when blood pressure is normalized. We hypothesized that intact mammalian target of rapamycin (mTOR) signaling is necessary for cardiac protection in females. We first tested sex differences and intracellular signaling after mTOR targeting with rapamycin in wild-type mice. Radio-telemetric blood pressure was maintained at normal for 6 weeks. Rapamycin significantly reduced left ventricular hypertrophy, preserved ejection fraction, inhibited fibrosis, and maintained capillary structure in male mice. Decreased mTORC1 and increased mTORC2 activity were detected in rapamycin-treated male mice compared with vehicle controls. In contrast, female mice developed dilative left ventricular hypertrophy, cardiac fibrosis, and capillary loss similar to DOCA-salt females lacking the estrogen receptor {beta} (ER{beta}(-/-)) that we described earlier. Because rapamycin downregulated ER{beta} in female mice, we next studied ER{beta}(-/-) normotensive DOCA-salt females. Vehicle-treated wild-type females maintained their high constitutive mTORC1 and mTORC2 in response to DOCA-salt. In contrast to males, both mTORCs were decreased by rapamycin, in particular mTORC2 by 60%. ER{beta}(-/-) DOCA-salt females showed similar mTORC1 and mTORC2 response patterns. We suggest that ERβ-dependent regulation involves sex-specific use of mTOR signaling branches. Maintenance of both mTORC1 and mTORC2 signaling seems to be essential for adaptive cardiac remodeling in females and supports a rationale for sex-specific therapeutic strategies in left ventricular hypertrophy

Autoantibodies targeting G protein-coupled receptors: An evolving history in autoimmunity. Report of the 4th international symposium

G protein-coupled receptors (GPCR) are involved in various physiological and pathophysiological processes. Functional autoantibodies targeting GPCRs have been associated with multiple disease manifestations in this context. Here we summarize and discuss the relevant findings and concepts presented in the biennial International Meeting on autoantibodies targeting GPCRs (the 4th Symposium), held in Lübeck, Germany, 15-16 September 2022. The symposium focused on the current knowledge of these autoantibodies' role in various diseases, such as cardiovascular, renal, infectious (COVID-19), and autoimmune diseases (e.g., systemic sclerosis and systemic lupus erythematosus). Beyond their association with disease phenotypes, intense research related to the mechanistic action of these autoantibodies on immune regulation and pathogenesis has been developed, underscoring the role of autoantibodies targeting GPCRs on disease outcomes and etiopathogenesis. The observation repeatedly highlighted that autoantibodies targeting GPCRs could also be present in healthy individuals, suggesting that anti-GPCR autoantibodies play a physiologic role in modeling the course of diseases. Since numerous therapies targeting GPCRs have been developed, including small molecules and monoclonal antibodies designed for treating cancer, infections, metabolic disorders, or inflammatory conditions, anti-GPCR autoantibodies themselves can serve as therapeutic targets to reduce patients' morbidity and mortality, representing a new area for the development of novel therapeutic interventions