Serpins and the Complement System

Beinrohr, László; Murray-Rust, Thomas A.; Dyksterhuis, Leanne B; Závodszky, Péter; Gál, Péter; Pike, Robert N.; Wijeyewickrema, Lakshmi C.

doi:10.1016/b978-0-12-386471-0.00004-3

Cited by 22 publications

(14 citation statements)

References 26 publications

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“…As mentioned earlier, a number of serpins were up-regulated. SERPING1, also known as C1-inhibitor, is an inhibitor of the complement system [ 53 ] and we confirmed protein expression through immunohistochemistry. Protein expression was strongest in luminal epithelial cells and slightly less pronounced in glandular epithelial cells.…”

Section: Discussionsupporting

confidence: 68%

Transcriptional profiling of equine endometrium before, during and after capsule disintegration during normal pregnancy and after oxytocin-induced luteostasis in non-pregnant mares

et al. 2021

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The current study used RNA sequencing to determine transcriptional profiles of equine endometrium collected 14, 22, and 28 days after ovulation from pregnant mares. In addition, the transcriptomes of endometrial samples obtained 20 days after ovulation from pregnant mares, and from non-pregnant mares which displayed and failed to display extended luteal function following the administration of oxytocin, were determined and compared in order to delineate genes whose expressions depend on the presence of the conceptus as opposed to elevated progesterone alone. A mere fifty-five transcripts were differentially expressed between samples collected from mares at Day 22 and Day 28 of pregnancy. This likely reflects the longer-term exposure to a relatively constant, progesterone-dominated environment with little change in factors secreted by the conceptus that would affect endometrial gene expression. The complement system was amongst the canonical pathways significantly enriched in transcripts differentially expressed between Day 14 and Day 22/28 of pregnancy. The expression of complement components 7 and 8 was confirmed using in situ hybridization. The expression of SERPING1, an inhibitor of the complement system, was confirmed by immunohistochemistry. In line with the resumed capacity of the endometrium to produce prostaglandin, prostaglandin G/H synthase 1 was expressed at higher levels at Days 22 and 28 than at Day 14 of pregnancy. Our data suggest that this up-regulation is enhanced by the presence of the conceptus; samples obtained from mares at Day 20 of pregnancy had significantly higher levels of prostaglandin G/H synthase 1 transcript than mares with extended luteal function.

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Section: Discussionsupporting

confidence: 68%

Transcriptional profiling of equine endometrium before, during and after capsule disintegration during normal pregnancy and after oxytocin-induced luteostasis in non-pregnant mares

et al. 2021

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“…Anti-inflammatory effects of heparins have been reported in vitro and in vivo, and are based on their role as a coadjuvant of serpins. 23 Reductions in inflammatory markers during administration of enoxaparin has also been reported in animal models. 24 These mechanisms also have a role in reduction of IL6 levels during inflammation induced by SARS-CoV2.…”

Section: Discussionmentioning

confidence: 92%

“…10,[25][26][27] Standard treatment for COVID-19 in fact is based on the administration of several kind of drugs with multiple actions, in order to reduce inflammatory damage (ie, antivirals, immunomodulants, antibiotics, steroids, antithrombotics). Due to their pharmacological properties, heparinoids can fight SARS-CoV2 in multiple ways: a specific antiviral action of heparin toward SARS-CoV2 has been found in vitro and in vivo, 10,[23][24][25][26][27] as well a specific anti-inflammatory action of heparinoids and fondaparinux. 28,29 Of course, these additional properties should be added to the well-known antithrombotic actions of both drugs.…”

Section: Discussionmentioning

confidence: 99%

Antithrombotic and Anti-Inflammatory Effects of Fondaparinux and Enoxaparin in Hospitalized COVID-19 Patients: The FONDENOXAVID Study

Cardillo¹,

Viggiano²,

Russo³

et al. 2021

JBM

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Background: Since the outbreak of novel coronavirus SARS-CoV2 around the world, great attention has been paid to the effects of such antithrombotic drugs as heparinoids, because they have antiviral action in vitro and antithrombotic actions in vivo. We conducted a retrospective analysis in inpatients with confirmed COVID-19 on the anti-inflammatory and antithrombotic effects of enoxaparin and fondaparinux at prophylactic doses. Methods: This retrospective cohort study used patients with confirmed COVID-19 during the first months of the Italian outbreak from February 18 to April 30, 2020. Our aim was to compare clinical characteristics, prophylactic treatment, markers of inflammation, and thrombotic outcomes in inpatients positive for SARS-CoV2 during hospitalization associated with thromboprophylaxis with enoxaparin (40 mg or 60 mg once daily) or fondaparinux (2.5 mg once daily). Statistical analysis was conducted with using MatLab R2016B and ad hoc functions. Results: There were no significatant differences in clinical characteristics between patients that used enoxaparin or fondaparinux as thromboprophylaxis for SARS-CoV2. No differences were found in D-dimer and fibrinogen levels either, which were used as markers of inflammation during the infection at testing on admission and after 3 weeks.Significant differences in CRP, IL6, and LDH were found in patients after 21 days' treatment. Discussion: Increased levels of fibrinogen and D-dimer in patients with confirmed COVID-19 have been reported in several studies. Our results showed that anti-inflammatory effects of fondaparinux and enoxaparin after 3 weeks of prophylactic treatment were similar when levels of fibrinogen and D-dimer were considered. Furthermore, levels of CRP showed a decrease in patients treated with enoxaparin and fondaparinux, although the decrease in the fondaparinux group seems to be more relevant.

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“…Increases in expression levels of such proteins have been observed in calcific (43) and stenotic (44,45) aortic valves. Such increases may lead to imbalances in lipid metabolism, increased inhibition of proteases such as antithrombins (46,47) with consequent regulation of complement activation (48,49). Overall, the proteomic data indicate that TVAL cells actively respond to TIC.…”

Section: Discussionmentioning

confidence: 90%

The tricuspid valve also maladapts: A multiscale study in sheep with biventricular heart failure

Meador

Mathur

Sugerman

et al. 2020

Preprint

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ObjectivesWe set out to determine the tricuspid valve’s propensity to (mal)adapt in disease.BackgroundTricuspid regurgitation (TR) is generally considered secondary to right and/or left ventricular disease without organic failure. Interestingly, we and others have previously shown the mitral valve (mal)adapts in functional mitral regurgitation, which may warrant reconsideration of its functional etiology. Whether the tricuspid valve similarly (mal)adapts is mostly unknown.MethodsWe evaluated the (mal)adaptive response of tricuspid valve anterior leaflets (TVALs) from an ovine model in which over-pacing (19 ± 6 days) induced biventricular heart failure and TR (tachycardia-induced cardiomyopathy, TIC, n=33) and compared findings to those from a control group (n=17). In both groups, we performed proteomics, immunohistochemistry, histology, two-photon microscopy, collagen assays, leaflet thickness and morphology measurements, and biaxial mechanical tests.ResultsWe found metabolically active resident valvular cells in TIC TVALs which expressed activation and turnover markers. In TIC TVALs, we observed a 140% increase in collagen content (p=0.016), increased collagen dispersion regionally (p=0.017), a 130% increase in leaflet area (p=0.002), a 140% increase in thickness (p=0.006), and a 130% increase in radial stiffness (p=0.006).ConclusionsOur data suggest that TVALs (mal)adapt during TIC on all scales. This response is likely initiated by activated valvular cells, resulting in collagen turnover, and ultimately leading to thickening, area increase, and stiffening. Our data motivates future studies on the exact pathways leading to tricuspid (mal)adaptation and pharmacological therapeutic strategies for TR.Condensed AbstractIn most cases, tricuspid regurgitation is presumed to originate from valve extrinsic factors. We challenge this paradigm and hypothesize that the tricuspid valve maladapts, rendering the valve at least partially culpable for its dysfunction. As such, we set out to demonstrate that the tricuspid valve, indeed, maladapts in an ovine model of heart disease. In the anterior leaflets, we found alterations on the protein and cell-level, leading to maladaptation in the form of tissue growth, thickening, and stiffening. Our findings may initially motivate mechanistic pathway studies, and in the future, leaflet-targeted pharmacological therapeutic options for tricuspid regurgitation.

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Serpins and the Complement System

Cited by 22 publications

References 26 publications

Transcriptional profiling of equine endometrium before, during and after capsule disintegration during normal pregnancy and after oxytocin-induced luteostasis in non-pregnant mares

Transcriptional profiling of equine endometrium before, during and after capsule disintegration during normal pregnancy and after oxytocin-induced luteostasis in non-pregnant mares

Antithrombotic and Anti-Inflammatory Effects of Fondaparinux and Enoxaparin in Hospitalized COVID-19 Patients: The FONDENOXAVID Study

The tricuspid valve also maladapts: A multiscale study in sheep with biventricular heart failure

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