“Osteotropic” Wnt/LRP Signals

Towler, Dwight A.

doi:10.1161/atvbaha.116.308915

Cited by 6 publications

(3 citation statements)

References 57 publications

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“…Boucher has hypothesized that while Wnt5a induction may initially provide an adaptive mechanism to limit intracellular cholesterol accumulation downstream of LRP1, with time the increased Wnt5a tone may promote cardiovascular calcification[132, 133]. This intriguing notion adds to accumulating data indicating that atheroma formation (atherosis) and arterial sclerosis (fibrosis, calcification, arterial stiffness) must be independently assessed to fully capture the impact of Wnt signaling and its modulation in atherosclerotic disease[134–136]. …”

Section: Introductionmentioning

confidence: 99%

“…For example, prolonged exposure to Dkk1 stabilizes LRP6 protein accumulation until Kremen2 engages Dkk1[149], and continuous Dkk1 exposure can result in “rebound” canonical signals in vitro [150]. Conversely, disease-dependent anatomical differences in VSM sclerostin epigenetic silencing may significantly shape the arterial dose-response relationship to antibody-mediated sclerostin inhibition [127, 136]. The extent to which this occurs in vivo has yet to be established, but points to how either sustained activation or inhibition of Wnt signaling programs may elicit time-dependent yet mechanism-based “toxicities” due to poorly established pharmacokinetic-pharmacodynamic relationships.…”

Section: Introductionmentioning

confidence: 99%

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Wnt signaling in cardiovascular disease: opportunities and challenges

Towler¹

2017

Current Opinion in Lipidology

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Purpose of review Cardiometabolic diseases increasingly afflict our aging, dysmetabolic citizenry. Complex signals regulating low density lipoprotein receptor-related protein (LRP) and frizzled protein family members – the plasma membrane receptors for the cadre of Wnt polypeptide morphogens – contribute to the control of cardiovascular homeostasis. Recent findings Both canonical (β-catenin-dependent) and noncanonical (β-catenin-independent) Wnt signaling programs control vascular smooth muscle cell (VSM) phenotypic modulation in cardiometabolic disease. LRP6 limits VSM proliferation, reduces arteriosclerotic transcriptional reprogramming, and preserves insulin sensitivity while LRP5 restrains foam cell formation. Adipose, skeletal muscle, macrophages and VSM have emerged as important sources of circulating Wnt ligands that are dynamically regulated during the prediabetes-diabetes transition with cardiometabolic consequences. Platelets release Dkk1, an LRP5/LRP6 inhibitor that induces endothelial inflammation and the prosclerotic endothelial-mesenchymal transition. By contrast, inhibitory secreted frizzled-related proteins shape the Wnt signaling milieu to limit myocardial inflammation with ischemia-reperfusion injury. VSM sclerostin, an inhibitor of canonical Wnt signaling in bone, restrains remodeling that predisposes to aneurysm formation, and is down-regulated in aneurysmal vessels by epigenetic methylation. Summary Components of the Wnt signaling cascade represent novel targets for pharmacological intervention in cardiometabolic disease. Conversely, strategies targeting the Wnt signaling cascade for other therapeutic purposes will have cardiovascular consequences that must be delineated to establish clinically useful pharmacokinetic – pharmacodynamic relationships.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Wnt signaling in cardiovascular disease: opportunities and challenges

Towler¹

2017

Current Opinion in Lipidology

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“…(1) BMP- and Wnt/β-Catenin-Signaling have been implicated in regulating osteochondrogenic differentiation of VSMC under calcifying conditions and to promote angiotensin II (AngII) induced aortic aneurysm (AA) (Freise et al 2016 ; Krishna et al 2017 ; Towler 2017 ). (2) Components of the inflammasomes, which mediate Caspase-1 dependent activation of interleukin 1β (IL-1β) and subsequent inflammatory cascade, have been shown to contribute to VSMC transformation and aortic aneurysms (Johnston et al 2013 , 2014 ).…”

Section: Introductionmentioning

confidence: 99%

Deficiency in Aim2 affects viability and calcification of vascular smooth muscle cells from murine aortas and angiotensin-II induced aortic aneurysms

Wortmann

Arshad

Hakimi

et al. 2020

Mol Med

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Background Phenotypic transformation of vascular smooth muscle cells is a key element in vascular remodeling and aortic aneurysm growth. Previously, deletion of several inflammasome components decreased formation of aortic aneurysm (AA) in the Angiotensin II (AngII) -induced mouse model. We hypothesized that the inflammasome sensor Absent in melanoma 2 (Aim2) might affect the phenotype of vascular smooth muscle cells (VSMC), thereby reducing AA formation. Methods Aim2−/− mice and wild-type (WT) C57Bl/6 J mice were used as an animal model. VSMC were isolated from 6 months old mice and grown in vitro. Young (passage 3–5) and senescent (passage 7–12) cells were analyzed in vitro for calcification in mineralization medium by Alizarin Red S staining. Expression of calcification and inflammatory markers were studied by real-time RT-PCR and Western blotting, release of cytokines was determined by ELISA. To induce AA, osmotic mini-pumps loaded with AngII (1500 ng/kg bodyweight/min) were implanted for 28 days in male mice at 6 months of age. Results Compared with VSMC from WT mice, VSMC isolated from Aim2−/− mice were larger, less viable, and underwent stronger calcification in mineralization medium, along with induction of Bmp4 and repression of Tnfsf11/Rankl gene expression. In addition, Aim2 deficiency was associated with reduced inflammasome gene expression and release of Interleukin-6. Using the mouse model of AngII induced AA, Aim2 deficiency reduced AA incidence to 48.4% (15/31) in Aim2−/− mice versus 76.5% (13/17) in WT mice. In contrast to Aim2−/− mice, AA from WT mice expressed significantly increased levels of alpha-smooth muscle actin/Acta2, indicating tissue remodeling. Reduced cell proliferation in Aim2−/− mice was indicated by significantly increased p16ink4a/Cdkn2a expression in untreated and AngII-infused aortas, and by significantly lower amounts of proliferating (Ki67 positive) VSMC in AngII-infused Aim2−/− mice. Conclusions Our results suggest a role for Aim2 in regulating VSMC proliferation and transition to an osteoblast-like or osteoclast-like phenotype, thereby modulating the response of VSMC in aortic remodeling and AA formation.

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Low-density lipoprotein receptor-related protein 6-mediated signaling pathways and associated cardiovascular diseases: diagnostic and therapeutic opportunities

Kang

2020

Hum Genet

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“Osteotropic” Wnt/LRP Signals

Cited by 6 publications

References 57 publications

Wnt signaling in cardiovascular disease: opportunities and challenges

Wnt signaling in cardiovascular disease: opportunities and challenges

Deficiency in Aim2 affects viability and calcification of vascular smooth muscle cells from murine aortas and angiotensin-II induced aortic aneurysms

Low-density lipoprotein receptor-related protein 6-mediated signaling pathways and associated cardiovascular diseases: diagnostic and therapeutic opportunities

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