Elastase-2, a Tissue Alternative Pathway for Angiotensin II Generation, Plays a Role in Circulatory Sympathovagal Balance in Mice

Becari, Christiane; Durand, M; Guimaraes, Alessander O.; Lataro, Renata Maria; Prado, Cibele M.; Oliveira, Mauro de; Candido, Sarai C. O.; Pais, Paloma; Ribeiro, Maurício Serra; Bäder, Michael; Pesquero, João Bosco; Salgado, Maria Cristina O.; Salgado, Hélio César

doi:10.3389/fphys.2017.00170

Cited by 5 publications

(4 citation statements)

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“…Echocardiography was performed in two distinct groups of mice, around 30 days after ligature, with a Vevo 2100 High-Resolution Imaging System (Visual Sonics, Toronto, ON, Canada), using a 30-MHz transducer. The steps and procedures were performed as previously described 32 . Briefly, mice were slightly anaesthetized using 1.5% isoflurane in 100% oxygen.…”

Section: Symbolic Analysis Of Hrvmentioning

confidence: 99%

Cardiovascular and Autonomic Dysfunction in Murine Ligature-Induced Periodontitis

Ribeiro

Santos-Júnior

Luiz

et al. 2020

Sci Rep

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the present study examined the hemodynamics [arterial pressure (Ap), Ap variability (ApV), heart rate (HR), and heart rate variability (HRV)], cardiac function (echocardiographycally), and myocardial inflammation in Balb/c mice submitted to Periodontitis, through the ligation of the left first molar, or Sham surgical procedure. The first protocol indicated that the AP was similar (136 ± 2 vs. 132 ± 3 mmHg in Sham), while the HR was higher in mice with Periodontitis (475 ± 20 vs. 412 ± 18 bpm in Sham), compared to their Sham counterparts. The APV was higher in mice with Periodontitis when evaluated in the time domain (4.5 ± 0.3 vs. 3.4 ± 0.2 mmHg in Sham), frequency domain (power of the LF band of systolic AP), or through symbolic analysis (patterns 0V + 1V), indicating a sympathetic overactivity. The HRV was similar in the mice with Periodontitis, as compared to their Sham counterparts. In the second protocol, the mice with Periodontitis showed decreased cardiac output (10 ± 0.8 vs. 15 ± 1.4 mL/ min in Sham) and ejection fraction (37 ± 3 vs. 47 ± 2% in Sham) associated with increased myocardial cytokines (Interleukin-17, Interleukin-6, and Interleukin-4). This study shows that experimental periodontitis caused cardiac dysfunction, increased heart cytokines, and sympathetic overactivity, in line with epidemiological studies indicating an increased risk of cardiovascular events in clinical periodontitis. Periodontitis is caused by a chronic inflammatory response to a periodontal biofilm that deranges the supporting tissues around the teeth (alveolar bone, periodontal ligament, and cementum), causing dental loss 1. This inflammatory disease represents a major public health problem, with an estimated prevalence of over 790 million people worldwide 2,3. Of note, more than 700 species of bacteria are estimated in the oral cavity forming the dental biofilm 4,5. Biofilms can release biologically active products, including bacterial lipopolysaccharides, chemotactic mediators, protein toxins, and organic acids. These active products elicit different components of innate and adaptive immunity 6 followed by the production of inflammatory mediators, mainly cytokines produced by immune cells 7. These cytokines, including interleukin (IL)-17, IL-6, IL-4, and other inflammatory mediators, such as C-reactive protein, are released in response to the stimuli induced by the dental biofilm 8. Different rodent models of periodontal disease have been described to investigate the pathophysiology of this inflammatory disease and accompanying complications 9,10. Nevertheless, the placement of a ligature around a molar tooth is one of the most widely used model 11. Indeed, ligatures around the posterior teeth mimic human periodontitis, leading to local inflammatory cell accumulation, apical migration of junctional epithelium, and bone loss 9,12,13. Moreover, the structure of the dental gingival area in the rodent is quite similar to that exhibited by humans 14. Recent studies have proven that the harmful effects of periodontitis are not re...

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Section: Symbolic Analysis Of Hrvmentioning

confidence: 99%

Cardiovascular and Autonomic Dysfunction in Murine Ligature-Induced Periodontitis

Ribeiro

Santos-Júnior

Luiz

et al. 2020

Sci Rep

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“…A previous study showed that ELA-2 KO promotes reduction in HR, changing the sympathovagal balance in mice and enhances the parasympathetic activity without affecting BP ( 11 ). ACE inhibition in ELA-2 KO mice caused a significant decrease in BP ( Figure 2 ) as expected, probably due to the withdrawal of two important routes of ANG II production.…”

Section: Discussionmentioning

confidence: 99%

“…ELA-2 knockout (ELA-2 KO) mice presented a lower heart rate (HR) compared with their wild-type counterparts. This strain shows changes in the autonomic balance, displaying increased parasympathetic flow, possibly due to the reduction of ANG II concentrations ( 11 ). However, the participation of ACE on the autonomic and hemodynamic profile of ELA-2 KO mice is still unknown.…”

Section: Introductionmentioning

confidence: 99%

Impact of angiotensin-converting enzyme inhibition on hemodynamic and autonomic profile of elastase-2 knockout mice

Prates-Costa

Oliveira

Fazan

et al. 2022

Braz J Med Biol Res

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Elastase-2 (ELA-2) is an angiotensin II-generating enzyme that participates in the cardiovascular system. ELA-2 is involved in hemodynamic and autonomic control and is upregulated in myocardial infarction and hypertension. The inhibition of angiotensin-converting enzyme (ACE) increased ELA-2 expression in the carotid arteries and heart of spontaneously hypertensive rats. In this study, we sought to investigate the role of ACE inhibition in hemodynamic and autonomic balance in elastase-2 knockout (ELA-2 KO) mice. Male ELA-2 KO and C57BL/6 mice were treated with the ACE inhibitor enalapril or saline for 10 days. After treatment, mice underwent surgery for cannulation of the femoral artery and arterial pressure recordings were made five days later in awake animals. The variability of systolic blood pressure (SBP) and pulse interval (PI) was evaluated in the time and frequency domain. Spontaneous baroreflex was assessed by the sequencing method. ACE inhibition caused a significant decrease in mean arterial pressure (117±2.2 vs 100±2.8 mmHg) and an increase in heart rate (570±32 vs 655±15 bpm) in ELA-2 KO mice. Despite a tendency towards reduction in the overall heart rate variability (standard deviation of successive values: 7.6±1.1 vs 4.7±0.6 ms, P=0.08), no changes were found in the root of the mean sum of squares or in the power of the high-frequency band. ACE inhibition did not change the spontaneous baroreflex indices (gain and baroreflex effectiveness index) in ELA-2 KO mice. Altogether, this data suggested that ACE played a role in the maintenance of hemodynamic function in ELA-2 KO mice.

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“…Animals: adult male and female ELA2KO (38 males/27 females) or C57BL6/j (33 males/33 females) mice, used as wild-type controls (WT), from 12-16 weeks of age at the beginning of the experiments, were employed. The ELA2KO were developed in the Max Delbrück Center for Molecular Medicine, Berlin, Germany; and the colony expanded in the Department of Physiology, at the University of São Paulo in Ribeirão Preto [21]. The animals were group housed, with free access to food and water, except during experimental sessions.…”

Section: Methodsmentioning

confidence: 99%

Elastase-2 Knockout Mice Display Anxiogenic- and Antidepressant-Like Phenotype: Putative Role for BDNF Metabolism in Prefrontal Cortex

et al. 2018

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Several pieces of evidence indicate that elastase-2 (ELA2; chymotrypsin-like ELA2) is an alternative pathway to the generation of angiotensin II (ANGII). Elastase-2 knockout mice (ELA2KO) exhibit alterations in the arterial blood pressure and heart rate. However, there is no data on the behavioral consequences of ELA2 deletion. In this study, we addressed this question, submitting ELA2KO and wild-type (WT) mice to several models sensitive to anxiety- and depression-like, memory, and repetitive behaviors. Our data indicates a higher incidence of barbering behavior in ELA2KO compared to WT, as well as an anxiogenic phenotype, evaluated in the elevated plus maze (EPM). While a decrease in locomotor activity was observed in ELA2KO in EPM, this feature was not the main source of variation in the other parameters analyzed. The marble-burying test (MBT) indicated increase in repetitive behavior, observed by a higher number of buried marbles. The actimeter test indicated a decrease in total activity and confirmed the increase in repetitive behavior. The spatial memory was tested by repeated exposure to the actimeter in a 24-h interval. Both ELA2KO and WT exhibited decreased activity compared to the first exposure, without any distinction between the genotypes. However, when submitted to the cued fear conditioning, ELA2KO displayed lower levels of freezing behavior in the extinction session when compared to WT, but no difference was observed during the conditioning phase. Increased levels of BDNF were found in the prefrontal cortex but not in the hippocampus of ELA2KO mice compared to WT. Finally, in silico analysis indicates that ELA2 is putatively able to cleave BDNF, and incubation of the purified enzyme with BDNF led to the degradation of the latter. Our data suggested an anxiogenic- and antidepressant-like phenotype of ELA2KO, possibly associated with increased levels of BDNF in the prefrontal cortex.

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Elastase-2, a Tissue Alternative Pathway for Angiotensin II Generation, Plays a Role in Circulatory Sympathovagal Balance in Mice

Cited by 5 publications

References 50 publications

Cardiovascular and Autonomic Dysfunction in Murine Ligature-Induced Periodontitis

Cardiovascular and Autonomic Dysfunction in Murine Ligature-Induced Periodontitis

Impact of angiotensin-converting enzyme inhibition on hemodynamic and autonomic profile of elastase-2 knockout mice

Elastase-2 Knockout Mice Display Anxiogenic- and Antidepressant-Like Phenotype: Putative Role for BDNF Metabolism in Prefrontal Cortex

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