Targeting Cadherin-11 Prevents Notch1-Mediated Calcific Aortic Valve Disease

Clark, Catherine L.; Bowler, Meghan; Snider, J. Caleb; Merryman, W. David

doi:10.1161/circulationaha.117.027771

Cited by 40 publications

(34 citation statements)

References 5 publications

(7 reference statements)

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“…These include in vitro models of calcification 59 and new genetic mouse models of CAVD. 60 In addition to potential in vivo imaging strategies in animal models, we showed that MAF quantification can be used to track nodule growth, non-invasively, over time in in vitro conditions. Nodules smaller than 10 microns in their cross-sectional width were imaged and showed growth overtime which we tracked in all three spatial dimensions over time.…”

Section: Discussionmentioning

confidence: 90%

Non-destructive two-photon excited fluorescence imaging identifies early nodules in calcific aortic-valve disease

et al. 2017

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Calcifications occur during the development of healthy bone, and at the onset of calcific aortic-valve disease (CAVD) and many other pathologies. Although the mechanisms regulating early calcium deposition are not fully understood, they may provide targets for new treatments and for early interventions. Here, we show that two-photon excited fluorescence (TPEF) can provide quantitative and sensitive readouts of calcific nodule formation, in particular in the context of CAVD. Specifically, by means of the decomposition of TPEF spectral images from excised human CAVD valves and from rat bone prior to and following demineralization, as well as from calcific nodules formed within engineered gels, we identified an endogenous fluorophore that correlates with the level of mineralization in the samples. We then developed a ratiometric imaging approach that provides a quantitative readout of the presence of mineral deposits in early calcifications. TPEF should enable non-destructive, high-resolution imaging of three-dimensional tissue specimens for the assessment of the presence of calcification.

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Section: Discussionmentioning

confidence: 90%

Non-destructive two-photon excited fluorescence imaging identifies early nodules in calcific aortic-valve disease

et al. 2017

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“…Previous studies have shown that genetic and pharmacologic targeting of CDH11 improves functional responses in both fibrotic lung disease and aortic valve calcification (10,11). Herein, CDH11 blockade by SYN0012 treatment appears to preserve cardiac function as early as 7 days after MI and prevents the continued functional decline observed with IgG2a treatment out to 56 days ( Figure 3A).…”

Section: Discussionmentioning

confidence: 65%

Cadherin-11 blockade reduces inflammation-driven fibrotic remodeling and improves outcomes after myocardial infarction

Schroer¹,

Bersi²,

Clark³

et al. 2019

JCI Insight

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“…Previous studies have shown that genetic and pharmacologic targeting of CDH11 improves functional responses in both fibrotic lung disease and aortic valve calcification. 8,9 Herein, CDH11 blockade preserves cardiac function as early as seven days after MI and prevents the continued functional decline up to 56 days after MI observed with IgG2a treatment (Figure 3A). LV volume was not different at seven days, but the dramatic increases in both diastolic and systolic volume between days seven and 56 in IgG2a-treated animals were prevented by pharmacological inhibition of CDH11 by SYN0012 (Figure 3C-D).…”

Section: Discussionmentioning

confidence: 95%

“…CDH11 engagement promotes the expression of the proinflammatory cytokine interleukin-6 (IL-6) as well as profibrotic signaling factors and myofibroblast markers, such as transforming growth factor beta 1 (TGF-β1), in diseased joints, lungs, and heart valves. [7][8][9][10][11] CDH11 (or OB-cadherin) was originally described in osteoblasts and has been shown to affect cell migration and exfiltration in cancer studies, 12,13 but the role of CDH11 in bone marrow-derived cell (BMDC) recruitment to the heart has not been studied. Thus, we hypothesized that genetic and pharmacologic targeting of CDH11 after MI would reduce inflammation-driven fibrotic scar expansion and improve cardiac outcomes.…”

Section: Introductionmentioning

confidence: 99%

Cadherin-11 Blockade Reduces Inflammation-Driven Fibrotic Remodeling and Improves Outcomes After Myocardial Infarction

Schroer

Bersi

Clark

et al. 2019

Preprint

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Background: Over one million Americans experience myocardial infarction (MI) every year, and the resulting scar and subsequent cardiac fibrosis contribute to heart failure and death. A specialized cell-cell adhesion protein, cadherin-11 (CDH11), contributes to inflammation and fibrosis in rheumatoid arthritis, pulmonary fibrosis, and aortic valve calcification but has not yet been studied in the context of cardiac remodeling after MI. We hypothesized that targeting CDH11 function after MI would reduce inflammation-driven fibrotic remodeling and infarct expansion to improve functional outcomes in mice.Methods: MI was induced by ligation of the left anterior descending artery in transgenic mice with reduced or ablated CDH11, wild type mice receiving bone marrow transplants from Cdh11 transgenic animals, and wild type mice treated with a functional blocking antibody against CDH11 (SYN0012). Cardiac function was measured by echocardiography, expression of cell populations was quantified by flow cytometry, and tissue remodeling by altered histological assessment and transcription of inflammatory and pro-angiogenic genes by qPCR. Co-culture was used to assess interactions between cardiac fibroblasts and macrophages.

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Targeting Cadherin-11 Prevents Notch1-Mediated Calcific Aortic Valve Disease

Cited by 40 publications

References 5 publications

Non-destructive two-photon excited fluorescence imaging identifies early nodules in calcific aortic-valve disease

Non-destructive two-photon excited fluorescence imaging identifies early nodules in calcific aortic-valve disease

Cadherin-11 blockade reduces inflammation-driven fibrotic remodeling and improves outcomes after myocardial infarction

Cadherin-11 Blockade Reduces Inflammation-Driven Fibrotic Remodeling and Improves Outcomes After Myocardial Infarction

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