Lenvatinib halts aortic aneurysm growth by restoring smooth muscle cell contractility

Busch, Albert; Pauli, Jessica; Winski, Greg; Bleichert, Sonja; Chernogubova, Ekaterina; Metschl, Susanne; Winter, Hanna; Trenner, Matthias; Wiegering, Armin; Otto, Christoph; Fischer, Johannes; Reiser, Judith; Werner, Julia; Roy, Joy; Brostjan, Christine; Knappich, Christoph; Eckstein, Hans‐Henning; Paloschi, Valentina; Maegdefessel, Lars

doi:10.1172/jci.insight.140364

Cited by 14 publications

(21 citation statements)

References 48 publications

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“…AngII stimulation resulted in greatly increased NUDT6 expression while reducing FGF2 levels (Figure 4B). Furthermore, primary aortic SMCs isolated from three different AAA patients, as previously described (33) showed a significant upregulation of NUDT6 with a concomitant reduction of FGF2 levels compared to commercially available hAoSMCs (Supplemental Figure 2A and B). This could be reversed by knocking down NUDT6 via siRNAs (Supplemental Figure 2C and D).…”

Section: Resultssupporting

confidence: 63%

“…One-year-old male LDLR - /- mini-pigs were fed a high-cholesterol Western diet for six months to trigger advanced atherosclerotic disease (Supplemental Figure 4A). AAAs for this study were induced via catheter-directed PPE infusion into the infrarenal section of the porcine aortas as previously described (32,33). Site-specific GapmeRs targeting porcine NUDT6 were tested in pig fibroblasts before application (Supplemental Figure 4B) to ensure sufficient knockdown.…”

Section: Resultsmentioning

confidence: 99%

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Targeting long non-coding RNANUDT6enhances smooth muscle cell survival and limits vascular disease progression

Winter

Winski

Busch

et al. 2022

Preprint

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Long non-coding RNAs (lncRNAs) orchestrate various biological processes and regulate the development of cardiovascular diseases. Their potential therapeutic benefit to tackle disease progression has recently been extensively explored. Our study investigates the role of lncRNA Nudix Hydrolase 6 (NUDT6) and its antisense target Fibroblast Growth Factor 2 (FGF2) in two vascular pathologies: abdominal aortic aneurysms (AAA) and carotid artery disease. Using tissue samples from both diseases, we detected a substantial increase of NUDT6, whereas FGF2 was downregulated. Targeting Nudt6 in vivo with antisense oligonucleotides in three murine and one porcine animal models of carotid artery disease and AAA limited disease progression. Restoration of FGF2 upon Nudt6 knockdown improved vessel wall morphology and fibrous cap stability. Overexpression of NUDT6 in vitro impaired smooth muscle cell (SMC) migration, while limiting their proliferation and augmenting apoptosis. By employing RNA pulldown followed by mass spectrometry as well as RNA immunoprecipitation, we identified Cysteine and Glycine Rich Protein 1 (CSRP1) as another direct NUDT6 interaction partner, regulating cell motility and SMC differentiation. Overall, the present study identifies NUDT6 as a well-conserved antisense transcript of FGF2. NUDT6 silencing triggers SMC survival and migration and could serve as a novel RNA-based therapeutic strategy in vascular diseases.

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Section: Resultssupporting

confidence: 63%

Section: Resultsmentioning

confidence: 99%

Targeting long non-coding RNANUDT6enhances smooth muscle cell survival and limits vascular disease progression

Winter

Winski

Busch

et al. 2022

Preprint

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“…For example, mTOR-dependent proliferative SMCs promote dilatation and dissection of the aortic wall rather than prevent disease progression, 36 and inhibition of tyrosine kinase mediated SMC proliferation and phenotypic switching by lenvatinib ameliorates AAA formation. 37 However, proliferation of SMCs is associated with their dedifferentiation, which potentially exerts detrimental effects in AAA development rather than the proliferative response per se.…”

Section: Discussionmentioning

confidence: 99%

PI 3-kinase isoform p110α controls smooth muscle cell functionality and protects against aortic aneurysm formation

Vantler

Schorscher

Berghausen

et al. 2022

Preprint

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Background: Catalytic class IA PI 3-kinase isoform p110alpha is a crucial regulator of cellular proliferation and survival in numerous cell types. While p110alpha is critically involved in pathogenic vascular remodeling, its physiological role for vascular integrity under stress conditions has not been studied. We report a protective function of smooth muscle p110alpha against abdominal aortic aneurysm (AAA) formation. Methods & Results: In mice lacking p110alpha in smooth muscle cells (sm-p110alpha-/-), perfusion of the infrarenal aorta with porcine pancreatic elastase (PPE) yielded substantially enhanced AAA formation compared to wild type controls. This disease phenotype is partly attributable to a subtle preexisting vascular phenotype under basal conditions, as sm-p110alpha-/- mice displayed a smaller media area, deranged aortic wall structure (detached smooth muscle cells, increased apoptotic cell death), and a diminished functional responsiveness of aortic rings to vasodilators. Furthermore, p110alpha is also implicated in regenerative processes during AAA development: Whereas wild type mice showed increased media hypertrophy, neointima formation and proliferation upon PPE intervention, these vascular remodeling processes were diminished in sm-p110alpha-/- mice. Concomitantly, increased numbers of elastic fiber breaks and ECM degradation were detected in sm-p110alpha-/- aorta. Mechanistically, we found that lack of p110alpha expression impaired smooth muscle cell proliferation, expression of contractile marker genes and production of elastin fibers. This phenotype largely depended on reduced phosphorylation and inactivation of FOXO1, as specific FOXO1 inhibition fully rescued proliferation of p110alpha-/- smooth muscle cells, and knockdown of FOXO1 increased expression of calponin and elastin. Conclusions: Smooth muscle p110alpha protects against AAA disease by maintaining aortic wall homoeostasis and promoting SMC proliferation to compensate for cell loss during AAA development. Our findings have potential implications for current approaches aimed at p110alpha inhibition for cancer therapy and suggest new pharmacological strategies to activate p110alpha signaling in AAA disease.

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“…Aneurysm growth and rupture after targeted radiation therapy of neighboring malignancies is almost exclusively reported for cranial arteries and only in singular case reports for non‐cranial locations (Pesce et al, 2020; Wohlauer et al, 2016). Considering that, that is, angiogenesis represents a common pathogenic feature, seen in both, cancer subtypes and aneurysms, the hypothesis that, that is, substances with anti‐angiogenic properties, such as tyrosine kinase inhibitors, might influence aneurysm growth is valid (Busch et al, 2017; Busch et al, 2021). Whether such targeted therapies might accelerate or stop aneurysm growth or influence the rupture rate is yet to be elucidated.…”

Section: Discussionmentioning

confidence: 99%

Concomitantly discovered visceral artery aneurysms do rarely grow during cancer therapy

et al. 2021

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Visceral artery aneurysms (VAA) are a rare entity of arterial aneurysms with the imminent threat of rupture. The impact of cancer and chemotherapy on the growth of VAAs is unknown. A retrospective dual center cohort study of patients with concomitant VAA and different types of cancer was conducted and the impact of various chemotherapeutic agents on VAA growth was studied by sequential CT analysis. For comparison, a non‐cancer all comer cohort with VAAs and no cancer was studied to compare different growth rates. The primary endpoint was aneurysm progress or regression >1.75 mm. Chi‐square test, Fisher's exact test and Mann–Whitney test was used for statistical comparison. In the 17‐year‐period from January 2003 to March 2020, 59 patients with 30 splenic artery aneurysms, 14 celiac trunk aneurysms, 11 renal artery aneurysms and 4 other VAA and additional malignancy were identified. 20% of patients suffered from prostate cancer, the rest were heterogeneous. The most prevalent chemotherapies were alkylating agents (23%), antimetabolites (14%) and mitose inhibitors (10%). Eight patients had relevant growth of their VAA and one patient showed diameter regression (average growth rate 0.1 ± 0.5 mm/year). Twenty‐nine patients with 14 splenic, 11 RAAs (seven right) and 4 celiac trunk aneurysms were available in the non‐cancer comparison cohort (average growth rate 0.5 ± 0.9 mm/year, p = 0.058). However, the growth rate of patients receiving operative treatment for relevant VAA growth was significantly higher (p = 0.004). VAAs grow rarely, and rather slow. Cancer and/or chemotherapy do not significantly influence the annual growth rate. Additional control examinations seem unnecessary.

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Lenvatinib halts aortic aneurysm growth by restoring smooth muscle cell contractility

Cited by 14 publications

References 48 publications

Targeting long non-coding RNANUDT6enhances smooth muscle cell survival and limits vascular disease progression

Targeting long non-coding RNANUDT6enhances smooth muscle cell survival and limits vascular disease progression

PI 3-kinase isoform p110α controls smooth muscle cell functionality and protects against aortic aneurysm formation

Concomitantly discovered visceral artery aneurysms do rarely grow during cancer therapy

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