Pro-apoptotic effect of anti-β1-adrenergic receptor antibodies in periodontitis patients (2023)

International Immunopharmacology

Volume 14, Issue 4,

December 2012

, 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 [1], [2], chagasic myocardiopathy [3], [4] and in patients suffering from chronic periodontal disease, with or without myocardial failure [5], [6].

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 [7], [8], [9] and a positive inotropic effect in isolated mice and rat atria [10], [11], but also induce dilated cardiomyopathy in animals following transfer of sera [7] or IgG [12] 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 [13] and calcium/calmodulin (CaM) complex [14], [15] and other signaling mechanisms identified as important second messengers regulating cardiac function [16].

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 [17]. 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 [18]. Norepinephrine and isoproterenol stimulate β1-AR and induce apoptosis in rat cardiomyocytes [19] 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 [20].

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 [21], [22]. 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 [23].

Cardiac apoptosis plays a key role in the pathogenesis of a variety of cardiovascular diseases, such as myocardial infarction [24], dilated cardiomyopathy [25], autoimmune cardiomyopathy [26] and heart failure [27]. 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 [24], [25], [26]. 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 [5], [6]. 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 [27], [28].

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.

Section snippets

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.

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      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 [8]. 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 [6].

      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.

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      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.

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      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 [19], and cAMP analogs could potentially be used as anti-cancer drugs [20,21].

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