AT1-receptor blockade, but not renin inhibition, reduces aneurysm growth and cardiac failure in fibulin-4 mice

Riet, Luuk te; Deel, Elza D. van; Thiel, Bibi S. van; Moltzer, Els; Vliet, Nicole van; Ridwan, Yanto; Veghel, Richard van; Heijningen, Paula M. van; Robertus, Jan Lukas; Garrelds, Ingrid M.; Vermeij, Marcel; Pluijm, Ingrid van der; Danser, A.H. Jan; Essers, Jeroen

doi:10.1097/hjh.0000000000000845

Cited by 16 publications

(10 citation statements)

References 56 publications

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“…These data show that Smad3 −/− animals experience rapid aneurysmal growth, and concurrent early death. Again, this is in contrast to Fibulin-4 R/R animals that are born with an aneurysm, which shows a slow but progressive growth with age (Te Riet et al, 2016). …”

Section: Resultsmentioning

confidence: 81%

Defective Connective Tissue Remodeling in Smad3 Mice Leads to Accelerated Aneurysmal Growth Through Disturbed Downstream TGF-β Signaling

et al. 2016

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Aneurysm-osteoarthritis syndrome characterized by unpredictable aortic aneurysm formation, is caused by SMAD3 mutations. SMAD3 is part of the SMAD2/3/4 transcription factor, essential for TGF-β-activated transcription. Although TGF-β-related gene mutations result in aneurysms, the underlying mechanism is unknown. Here, we examined aneurysm formation and progression in Smad3−/− animals.Smad3−/− animals developed aortic aneurysms rapidly, resulting in premature death. Aortic wall immunohistochemistry showed no increase in extracellular matrix and collagen accumulation, nor loss of vascular smooth muscle cells (VSMCs) but instead revealed medial elastin disruption and adventitial inflammation. Remarkably, matrix metalloproteases (MMPs) were not activated in VSMCs, but rather specifically in inflammatory areas. Although Smad3−/− aortas showed increased nuclear pSmad2 and pErk, indicating TGF-β receptor activation, downstream TGF-β-activated target genes were not upregulated. Increased pSmad2 and pErk staining in pre-aneurysmal Smad3−/− aortas implied that aortic damage and TGF-β receptor-activated signaling precede aortic inflammation. Finally, impaired downstream TGF-β activated transcription resulted in increased Smad3−/− VSMC proliferation.Smad3 deficiency leads to imbalanced activation of downstream genes, no activation of MMPs in VSMCs, and immune responses resulting in rapid aortic wall dilatation and rupture. Our findings uncover new possibilities for treatment of SMAD3 patients; instead of targeting TGF-β signaling, immune suppression may be more beneficial.

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Section: Resultsmentioning

confidence: 81%

Defective Connective Tissue Remodeling in Smad3 Mice Leads to Accelerated Aneurysmal Growth Through Disturbed Downstream TGF-β Signaling

et al. 2016

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“…In view of all these considerations, the failure of TGF-β-neutralizing antibody treatment to suppress p-Smad2/3 and ameliorate disease in LDS mouse models seems more likely to be explained by issues related to bioavailability, as also observed in other TGF-β-related pathologies (76), rather than inferences regarding loss or gain of TGF-β activity in the pathogenesis and treatment of disease (22)(23)(24). While protective therapeutic trials in preclinical models associate with attenuation of biochemical and gene expression signatures indicative of TGF-β signaling (19,48,(52)(53)(54)(55)(56), ambiguity remains as to the relative contribution of TGF-β inhibition to disease amelioration, and the role of TGF-β signaling as a primary driver or a nonspecific late-stage consequence of disease (21,24,46,56,57). Ongoing controversy has also been fueled by the observation that genetic abrogation of TGF-β signaling in VSMCs can result in severe and widespread aortopathy, or exacerbation of vessel wall disruption caused by other insults such as AngII infusion or genetic predisposition for aneurysm (58)(59)(60)(61)(62)(63)(64)(65).…”

Section: Discussionmentioning

confidence: 99%

Lineage-specific events underlie aortic root aneurysm pathogenesis in Loeys-Dietz syndrome

MacFarlane¹,

Parker²,

Shin

et al. 2019

Journal of Clinical Investigation

103

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“…FBLN4 is essential for connective tissue development and elastic fiber formation, and it plays an important role in vascular patterning and collagen biosynthesis 37. Moreover, it is involved in the onset and progression of many diseases, including aortic aneurysms,38,39 cutis laxa,40,41 and osteoarthritis 42. FBLN4 has been observed to be a specific protein partner for mutant p53, and it displays both mutant p53-dependent and -independent oncogenic properties, with implications for both cancer biology and therapeutic intervention.…”

Section: Discussionmentioning

confidence: 99%

<em>FBLN4</em> as candidate gene associated with long-term and short-term survival with primary glioblastoma

Li¹,

Li²,

Zhang³

et al. 2017

OTT

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BackgroundGlioblastoma multiforme (GBM) is the most common malignant and lethal type of primary central nervous system tumor in humans. In spite of its high lethality, a small percentage of patients have a relatively good prognosis, with median survival times of 36 months or longer. The identification of clinical subsets of GBM associated with distinct molecular genetic profiles has made it possible to design therapies tailored to treat individual patients.MethodsWe compared microarray data sets from long-term survivors (LTSs) and short-term survivors (STSs) to screen for prognostic biomarkers in GBM patients using the WebArrayDB platform. We focused on FBLN4, IGFBP-2, and CHI3L1, all members of a group of 10 of the most promising, differentially regulated gene candidates. Using formalin-fixed paraffin-embedded GBM samples, we corroborated the relationship between these genes and patient outcomes using methylation-specific polymerase chain reaction (PCR) for MGMT methylation status and quantitative reverse transcription PCR for expression of these genes.ResultsExpression levels of the mRNAs of these 3 genes were higher in the GBM samples than in normal brain samples and these 3 genes were significantly upregulated in STSs compared to the levels in LTS samples (P<0.01). Furthermore, Kaplan–Meier analysis showed that the expression patterns of FBLN4 and IGFBP-2 serve as independent prognostic indicators for overall survival (P<0.01 and P<0.05, respectively).ConclusionTo our knowledge, this is the first report describing FBLN4 as a prognostic factor for GBM patient survival, demonstrating that increased GBM survival time correlates with decreased FBLN4 expression. Understanding FBLN4 expression patterns could aid in the creation of powerful tools to predict clinical prognoses of GBM patients.

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AT1-receptor blockade, but not renin inhibition, reduces aneurysm growth and cardiac failure in fibulin-4 mice

Cited by 16 publications

References 56 publications

Defective Connective Tissue Remodeling in Smad3 Mice Leads to Accelerated Aneurysmal Growth Through Disturbed Downstream TGF-β Signaling

Defective Connective Tissue Remodeling in Smad3 Mice Leads to Accelerated Aneurysmal Growth Through Disturbed Downstream TGF-β Signaling

Lineage-specific events underlie aortic root aneurysm pathogenesis in Loeys-Dietz syndrome

<em>FBLN4</em> as candidate gene associated with long-term and short-term survival with primary glioblastoma

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