Volume 14, Issue 4,
, Pages 710-721
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An anti-β1-adrenergic antibody from the sera of periodontitis patients (anti-β1-AR IgG) against the second extracellular loop of the human β1-adrenoceptor (β1-AR) has been shown to cause rat atria apoptosis. The anti-β1-AR IgG binds and activates atria β1-AR, increasing the intracellular calcium concentration, which, in turn, activates caspases-3, -8, and -9. The β1-AR and the post-receptor activation of calcium/calmodulin (CaM) lead to increased inducible nitric oxide synthase (iNOS) activity, with an increase in cyclic GMP (cGMP) accumulation as well as increased JNK phosphorylation and cyclic AMP (cAMP) production. We also observed an apoptotic effect of anti-β1-AR IgG, with increased generation of PGE2. Comparatively, xamoterol, an authentic β1-AR agonist, mimicked the autoantibody effect on rat atria β1-AR apoptosis. Our results suggest that autoantibodies from the sera of periodontitis patients bind and interact with rat atria β1-AR, provoking apoptosis. This implicates a series of modulatory cardiac signaling events that could alter normal heart function and may occur with chronic stimulation of the atria β1-AR, which could lead to heart failure. These results suggest an important link between periodontitis and cardiovascular disease.
► Sera IgG from periodontitis patients against human β1-adrenoceptor was identified. ► Anti-β1-adrenergic IgG causes rat atria apoptosis through caspase activities. ► An important link between periodontitis and cardiovascular disease was discussed.
Autoimmune cardiomyopathy has gained increased recognition as an important cause of human dilated cardiomyopathy. Among the anti-cardiac autoantibodies, antibodies against the β1-adrenoceptor (β1-AR) have been detected in patients with idiopathic dilated cardiomyopathy , , chagasic myocardiopathy ,  and in patients suffering from chronic periodontal disease, with or without myocardial failure , .
Anti-β1-adrenoceptor IgG (anti-β1-AR IgG) appears to be pathophysiologically important because these antibodies not only exert direct apoptotic and negative inotropic effects in cultured cardiomyocytes , ,  and a positive inotropic effect in isolated mice and rat atria , , but also induce dilated cardiomyopathy in animals following transfer of sera  or IgG  from diseased animals. Because the effects of anti-β1-AR IgG appear to be mediated via the myocardium β1-adrenoceptors (β1-AR) and these antibodies are capable of binding and interacting with myocardial β1-AR, there is also a functional link to β1-AR-mediated activation of cardiac adenylate cyclase  and calcium/calmodulin (CaM) complex ,  and other signaling mechanisms identified as important second messengers regulating cardiac function .
The positive inotropic effect of β1-AR stimulation is an effective measure for maintaining cardiac output by activation of protein kinase A through G-proteins, adenylate cyclase, and cyclic AMP . However, long-term stimulation of β1-AR can lead to deterioration in cardiac function and one mechanism that may contribute to this is thought to be the induction of apoptosis on β1-AR stimulation . Norepinephrine and isoproterenol stimulate β1-AR and induce apoptosis in rat cardiomyocytes  and the role of nitric oxide (NO) as a messenger, and also as an effector molecule, affects programmed cell death through cyclic guanosine monophosphate (cGMP)-dependent and -independent pathways .
Apoptosis is a highly regulated process in which pro-death and pro-survival cell signals are regulated and integrated to determine the fate of a cell. In fact, in the mitochondrial-mediated intrinsic pathway, stimuli lead to the release of mitochondrial membrane proteins that assemble into an apoptosome, which ultimately activates caspase that are mediators of cell death , . Potent proteases, like caspase-3, break up sub-cellular cytoplasmic and nuclear proteins. Caspase-8, associated with cytokines, is associated with the extracellular pathway, which follows mitochondrial events via the release of cytochrome c into the cytoplasm and activation of caspase-9. All these pathways finally converge on the terminal or executioner caspase, which mediate the final steps of apoptosis .
Cardiac apoptosis plays a key role in the pathogenesis of a variety of cardiovascular diseases, such as myocardial infarction , dilated cardiomyopathy , autoimmune cardiomyopathy  and heart failure . It is also a highly regulated program of cell death and inhibition of this process is cardio protective under many conditions.
Periodontitis is characterized by gingival inflammation and periodontopathic bacteria generate immunological inflammatory responses. Periodontitis is a key risk factor for the onset of cardiovascular disease , , . Recently, we reported that in the sera of periodontitis patients we found autoantibodies against atria cardiac β1-AR that were able to mimic the effect of an authentic β1-AR agonist acting on atria β1-AR , . However, the release of host-derived inflammatory mediators, such as cytokines from chronically inflamed periodontal tissues, into the circulation together with the sera anti-β1-AR IgG, may provide a link between periodontal disease and cardiovascular disease , .
In this paper, we will discuss (a) the effect of anti-β1-AR IgG acting on β1-AR in rat atria and its capacity to activate caspase pathway, (b) molecular signals involved in anti-β1-AR IgG – β1-AR-stimulated myocardium apoptosis and increased cAMP production and JNK phosphorylation, and (c) the role of anti-β1-AR IgG in the release of inflammatory mediators (PGE2, NO, cGMP) that participate in atria β1-AR-stimulated cardiomyocytes apoptosis.
Ethical approval of the study protocol
The study protocol complied with the tenets of the Declaration of Helsinki and the rules established by the Ethics Committee of the University of Buenos Aires (Buenos Aires, Argentina). All subjects provided written informed consent.
The study group consisted of 16 adult patients with periodontitis who were attending the Periodontology Clinic from the metropolitan area of Buenos Aires. The mean age was 41 (range, 32-50) years. Healthy subjects were used as controls (15 male subjects) with a mean
Rat atria apoptotic nuclei
We initially determined comparatively the stimulatory effect of the different concentrations of xamoterol (a β1-specific agonist; Fig.1A) and periodontal anti-β1-AR IgG (Fig.1B) in rat atria apoptotic nuclei. We found that xamoterol caused a marked increase in the number of apoptotic atria nuclei, as shown by the TUNEL assay (Fig.1A) and maximal effect of the β1-specific agonist was obtained at 1×10−8M. Fig.1A also shows the lack of action of xamoterol in the presence of 1×10−7M atenolol, a
In the present study, we investigated the effects of anti-β1-AR IgG from the sera of periodontitis patients and its role on atria β1-AR-mediated regulation of cardiomyocyte apoptosis. We demonstrated that the antibody against β1-AR is capable of activating the caspase (3, 9, and 8) pathway and also that the β1 autoantibody has the ability to trigger increased production of NO and PGE2. On the other hand, xamoterol, an authentic β1-AR agonist, mimicked the effects of anti-β1-AR IgG on the β1-AR
This work was supported by grants from Buenos Aires University (grant number UBACyT O 003) and the National Research & Technology Agency (PICT 01647). We thank Mrs. Elvita Vannucchi and Mr. Alejandro Thorton for their expert technical assistance. The authors declare that they have no conflict of interest.
- M. Iwata et al.
Autoantibodies against the second extracellular loop of beta1-adrenergic receptors predict ventricular tachycardia and sudden death in patients with idiopathic dilated cardiomyopathy
J Am Coll Cardiol
- E.S. Borda et al.
Antiadrenergic and muscarinic receptor antibodies in Chagas' cardiomyopathy
Int J Cardiol
- J. Liu et al.
Adoptive passive transfer of rabbit beta1-adrenoceptor peptide immune cardiomyopathy into the Rag2−/− mouse: participation of the ER stress
J Mol Cell Cardiol
- L. Sterin-Borda et al.
Chagasic IgG binds and interacts with cardiac beta adrenoceptor-coupled adenylate cyclase system
Int J Immunopharmacol
- L. Joensen et al.
Trypanosoma cruzi antigen that interacts with the beta1-adrenergic receptor and modifies myocardial contractile activity
Mol Biochem Parasitol
- J.M. Adams et al.
Life-or-death decisions by the Bcl-2 protein family
Trends Biochem Sci
- H. Parlakpinar et al.
Protective effect of caffeic acid phenethyl ester (CAPE) on myocardial ischemia–reperfusion-induced apoptotic cell death
- V. Sharma et al.
Metoprolol increases the expression of beta(3)-adrenoceptors in the diabetic heart: effects on nitric oxide signaling and forkhead transcription factor-3
Eur J Pharmacol
- X. Liu et al.
Induction of apoptotic program in cell-free extracts: requirement for dATP and cytochrome c
- T.M. Lincoln et al.
Cyclic GMP-dependent protein kinase in nitric oxide signaling
Prostaglandin E2 induced caspase-dependent apoptosis possibly through activation of EP2 receptors in cultured hippocampal neurons
Glycogen synthase kinase-3beta plays a pro-apoptotic role in beta-adrenergic receptor-stimulated apoptosis in adult rat ventricular myocytes: role of beta1 integrins
J Mol Cell Cardiol
Autoantibodies against β-adrenoceptors in human idiopathic dilated cardiomyopathy
Antibodies to beta 1 and beta 2 adrenoreceptors in Chagas' disease
Clin Exp Immunol
Human chagasic IgG interacting with lymphocyte neurotransmitter receptors triggers intracellular signal transduction
Role of anti-β(1)adrenergic antibodies from patients with periodontitis in cardiac dysfunction
J Oral Pathol Med
Autoantibodies to the β(1)-adrenoceptor from patients with periodontitis as a risk factor for cardiac dysfunction
Direct evidence for a beta 1-adrenergic receptor-directed autoimmune attack as a cause of idiopathic dilated cardiomyopathy
J Clin Invest
Autoantibodies activating human beta1-adrenergic receptors are associated with reduced cardiac function in chronic heart failure
Anti-beta(1)-adrenergic receptor antibodies and heart failure: causation, not just correlation
J Clin Invest
Alterations in cardiac beta-adrenergic receptors in chagasic mice and their association with circulating beta-adrenoceptor-related autoantibodies
Cardiomyocyte apoptosis in autoimmune cardiomyopathy: mediated via endoplasmic reticulum stress and exaggerated by norepinephrine
Am J Physiol Heart Circ Physiol
Linkage of beta1-adrenergic stimulation to apoptotic heart cell death through protein kinase A-independent activation of Ca2+/calmodulin kinase II
J Clin Invest
The adenylyl cyclases as integrators of transmembrane signal transduction
Norepinephrine stimulates apoptosis in adult rat ventricular myocytes by activation of the beta-adrenergic pathway
Inducible cAMP early repressor (ICER) is a negative-feedback regulator of cardiac hypertrophy and an important mediator of cardiac myocyte apoptosis in response to beta-adrenergic receptor stimulation
Nitric oxide: promoter or suppressor of programmed cell death?
Effects of chronic Porphylomonas gingivalis lipopolysaccharide infusion on cardiac dysfunction in mice
2021, Journal of Oral Biosciences
Citation Excerpt :
It has been reported that β1-AR antibodies induce myocardial apoptosis in patients with PD. In a study on rats showed that a β1-AR blocker prevented the induction of myocardial apoptosis . Patients with PD whose sera are reactive with a β1-AR synthetic peptide have an enhanced heart rate and decreased heart rate variability; which is a risk factor for the development of CVD and may indicate a profound alteration of sympathetic nerve activity .
Periodontitis (PD) is a chronic inflammatory disease of tooth-supportive tissue. An association between PD and cardiovascular disease (CVD) has been established. Although PD is generally accepted as a risk factor for CVD, the existence of a relationship remains debatable. Possible mechanisms include the release of inflammatory mediators such as lipopolysaccharide (LPS), which may spread systemically and promote CVD.
To compare the effects of lipopolysaccharide derived from Porphylomonas gingivalis (PG-LPS) on cardiac muscle in mice, mice were treated for 1 week with/without PG-LPS at a dose equivalent to the circulating level in PD patients (0.8mg/kg/day).
Cardiac function in terms of left ventricular ejection function was significantly decreased at 1 week compared to that in the control (from 66±0.5% to 57±1.1%). Compared to the controls, the number of apoptotic myocytes and the area of fibrosis were significantly increased by approximately 2.7-fold and 14-fold, respectively. The impairment of cardiac function appeared to involve the activation of cAMP/PKA signaling and cAMP/calmodulin kinase II signaling (CaMKII), leading to cardiac fibrosis, myocyte apoptosis and heart failure.
Our results indicate that cAMP/PKA and cAMP/CaMKII signaling may be a new therapeutic target for the treatment of cardiovascular diseases in patients with periodontitis.
MiR-181b promotes cell proliferation and reduces apoptosis by repressing the expression of adenylyl cyclase 9 (AC9) in cervical cancer cells
2014, FEBS Letters
Citation Excerpt :
Cyclic AMP (cAMP) is produced from ATP by 10 different isoforms of AC in mammals, including the membrane-bound AC1-AC9 isoforms and a soluble AC isoform, and can be degraded into 5′-AMP by phosphodiesterases [12–14]. As a second messenger, cAMP can either stimulate or inhibit apoptosis [15–18]. In HeLa cells, cAMP inhibits cell growth and promotes apoptosis , and cAMP analogs could potentially be used as anti-cancer drugs [20,21].
MicroRNAs are a class of small, endogenous, non-coding RNAs that function as post-transcriptional regulators. In this study, we found that miR-181b promoted cell proliferation and inhibited cell apoptosis in cervical cancer cells. And we validated a new miR-181b target gene, adenylyl cyclase 9 (AC9). miR-181b restricted cAMP production by post-transcriptionally downregulating AC9 expression. Phenotypic experiments indicated that miR-181b and AC9 exerted opposite effects on cell proliferation and apoptosis.
Endoplasmic reticulum stress contributed to β<inf>1</inf>-adrenoceptor autoantibody-induced reduction of autophagy in cardiomyocytes
2019, Acta Biochimica et Biophysica Sinica
2019, Frontiers in Bioscience - Landmark
Roles of the protein tyrosine phosphatase PTPN22 in immunity and autoimmunity
Clinical Immunology, Volume 149, Issue 3, Part B, 2013, pp. 556-565
PTPN22 is a protein tyrosine phosphatase expressed by the majority of cells belonging to the innate and adaptive immune systems. Polymorphisms in PTPN22 are associated with several autoimmune diseases, such as systemic lupus erythematosus, rheumatoid arthritis and type 1 diabetes. This review discusses the role of PTPN22 in T and B cells, and its function in innate immune cells, such as monocytes, dendritic cells and NK cells. We focus particularly on the complexity that underlies the function of PTPN22 in the biological processes of the immune system; such complexity has led various research groups to produce rather conflicting data.
Misoprostol treatment for early pregnancy loss: an international survey
Reproductive BioMedicine Online, Volume 42, Issue 5, 2021, pp. 997-1005
What is the global variability in misoprostol treatment for the management of early pregnancy loss (EPL)?
An international web-based survey of fertility specialists and obstetrics and gynaecology clinicians was conducted between August and November 2020. The survey consisted of 16 questions addressing several aspects of misoprostol treatment for EPL.
Overall, 309 clinicians from 80 countries participated in the survey, of whom 67.3% were fertility specialists. Nearly one-half (47.9%) of the respondents let the patient choose the first line of treatment (expectant management, misoprostol treatment or surgical aspiration) according to her own preference. The 248 respondents who administer misoprostol in their daily practice were asked further questions; 59.7% of them advise patients to take the medication at home. The most common dose and route of administration is 800 µgadministered vaginally. Only 28.6% of participants use mifepristone pretreatment. Variation in the timing of the first follow-up visit after misoprostol administration was wide, ranging from 24 h to 1 week in most clinics. In case of incomplete expulsion, only 42.3% of the respondents routinely administer a second dose. The timing of the final visit and the definition of successful treatment also differed greatly among respondents.
There is large variability in the use of misoprostol for the management of EPL. High-quality research is necessary to examine several aspects of the treatment. Particularly, the timing and effectiveness of a second dose administration and the criteria to decide on treatment failure or success deserve more research in the future.
Formation and use of anaerobic consortia for the biotransformation of sulfur-containing extracts from pre-oxidized crude oil and oil fractions
Bioresource Technology, Volume 319, 2021, Article 124248
A new solution for fossil raw materials desulfurization based on a hybrid chemical-biocatalytic scheme with biogas and sulfide production is proposed.·H2O2, formic acid and Na2MoO4 were used for petroleum or oil fractions pre-oxidation. Ethanol or dimethylformamide was used as extractant to remove sulfur-contained compounds from pre-oxidized straight-run diesel oil fraction, non-hydro treated vacuum gas oil, gas condensate or crude oil. Compositions of cells (anaerobic sludge, Desulfovibrio vulgaris, Clostridium acetobutilycum, Rhodococcus ruber, Rhodococcus erythropolis) were specially developed, immobilized in poly(vinyl alcohol) cryogel and used for methanogenic treatment of sulfur-containing extracts, diluted with phosphate buffer (pH 7.2) and hydrolysates of renewable raw materials. The sulfur coming into the reactor with the extracts was 100% converted to inorganic sulfide or cell biomass. The ratio of methane in the biogas was 68–76%. Bioluminescent express-methods were used to control the possible toxicity of media and metabolic activity of cells used as biocatalysts.
Epidemiology of Chronic Pain in the Latium Region, Italy: A Cross-Sectional Study on the Clinical Characteristics of Patients Attending Pain Clinics
Pain Management Nursing, Volume 20, Issue 4, 2019, pp. 373-381
In Italy, chronic pain affects more than a quarter of the population, whereas the average European prevalence is 21%. This high prevalence might be due to the high percentage of Italian people who do not receive treatment, even after the passing of law 38/2010 (the right to access pain management in Italy), which created a regional network for the diagnosis and treatment of noncancer chronic pain. Italian epidemiologic studies on chronic pain are scanty, and this observational, multicenter, cross-sectional study is the first to investigate the clinical characteristics of patients who attended the pain management clinics in the Latium Region, Italy, for the management of their noncancer chronic pain. A total of 1,606 patients (mean age 56.8years, standard deviation±11.4), 67% women, were analyzed. Severe pain was present in 54% of the sample. Women experienced pain and had it in two or more sites more often than men (57% vs. 50%, p=.02; and 55.2% vs. 45.9%, p<.001, respectively). Chronic pain was musculoskeletal (45%), mixed (34%), and neuropathic (21%). In more than 60% of the cases, chronic pain was continuous, and in 20% it had lasted for more than 48months; long-lasting pain was often neuropathic. Low back (33.4%) and lower limbs (28.2%) were the main locations. Severe intensity of pain was statistically significantly associated with female gender (odds ratio [OR] 1.39; 95% confidence interval [CI] 1.06-1.84); with International Classification of Diseases, Ninth Revision, codes for chronic pain syndrome (OR 2.14; 95% CI 1.55-2.95); and with continuous pain (OR 2.02; 95% CI 1.54-2.66). Neuropathic pain and mixed pain were significantly associated with number of sites, and a trend seemed to be present (OR 2.11 and 3.02 for 2 and 3+sites; 95% CI 1.59-2.79 and 2.00-4.55, respectively).
How to manage lymphoid malignancies during novel 2019 coronavirus (CoVid-19) outbreak: a Brazilian task force recommendation
Hematology, Transfusion and Cell Therapy, Volume 42, Issue 2, 2020, pp. 103-110
The novel Coronavirus (CoVid-19) outbreak is now consider a world pandemic, affecting more than 1,300,000 people worldwide. Cancer patients are in risk for severe disease, including a higher risk of intensive care unit (ICU) admission, need for invasive ventilation or death. Management of patients with lymphoid malignancies can be challenging during the outbreak, due to need of multiple hospital visits and admissions, immunosuppression and need for chemotherapy, radiotherapy and stem cell transplantation. In this article, we will focus on the practical management of patients with lymphoid malignancies during the COVID-19 pandemic, focusing on minimizing the risk for patients.
A recyclable CNC-milled microfluidic platform for colorimetric assays and label-free aged-related macular degeneration detection
Sensors and Actuators B: Chemical, Volume 290, 2019, pp. 484-492
We report the development of a simple, low-cost, and eco-friendly stand-alone 3D microfluidic chemical sensing platform capable of colorimetric and biochemical analyses at the same time. The microfluidic cellulose microfiber (μCM) chip was prototyped by injecting 10% CM mixtures on computer numeric control (CNC)-milled substrates. We show that the μCM chip has a 3-fold faster flow rate than conventional microfluidic paper-based analytical devices and is a recyclable platform that could perform basic microfluidic experiments. The colorimetric assays of the μCM chip can successfully detect clinically relevant concentrations of albumin (R2 = 0.9994) and glucose (R2 = 0.9464). The gold nanoparticle-induced surface-enhanced Raman scattering (SERS) label-free bioassay of μCM chips can enhance the Raman signal by 5.15 × 108 and a sensitivity of 0.94 (10 pM–1 mM for CV molecules) with an excellent stability of <5%. We can detect the presence of exudative age-related macular degeneration (AMD) from human aqueous humors with >96% clinical sensitivity and >78% clinical specificity (87% accuracy) from principal component linear discriminant analysis (PC-LDA) model-based multivariate statistical analysis methods.
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