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Inhibition of the multifunctional homeodomain-interacting protein kinase 2 (HIPK2) alleviates thoracic aortic disease in mice with progressively severe Marfan syndrome

ABSTRACT: Thoracic aortic aneurysm (TAAs) are a severe complication in Marfan Symdrome (MFS), often leading to dissection and premature death. To identify potential drug targets for the treatment for TAAs we used gene expression profiles from MFS mice and patients to predict kinases that regulate gene expression. Among the top predictions was the kinase HIPK2. Ubiquitous post-natal inactivation of the HIPK2 gene, as well as chronic administration of an allosteric inhibitor of HIPK2/Smad3 interaction, increased the survival of MFS mice and improved multiple surrogate parameters.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE145903 | GEO | 2021/10/27

REPOSITORIES: GEO

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Inhibition of Intimal CX3CR1+ Macrophages Mitigates Thoracic Aortic Aneurysm Progression in Marfan Syndrome

Project description:Current understanding on the pathogenesis of thoracic aortic aneurysms (TAAs) in Marfan Syndrome (MFS) mainly focuses on vascular smooth muscle cell (VSMC) pathologies. Whether immune cell-mediated inflammation drives the progression of TAAs is still elusive. Using single-cell RNA sequencing, a subset of macrophages highly expressing CX3CR1 and mainly locating in the aortic intima was identified in aortic root and ascending aortas from Fbn1C1041G/+ mice, and further validated in MFS patients. Specific elimination of CX3CR1+ macrophages by diphtheria toxin in Cx3cr1-CreERT2iDTRF/+Fbn1C1041G/+ mice efficiently ameliorated TAA progression, suggesting their pathogenic action. Using monoclonal antibodies Adalimumab and Teprotumumab to respectively neutralize the proinflammatory cytokines TNFalpha and IGF1 produced by CX3CR1+ macrophages from MFS patients substantially suppressed CX3CR1+ macrophage-mediated inflammation in MFS patient-specific induced pluripotent stem cell (iPSC)-derived VSMCs. Furthermore, bone marrow transplantation and parabiosis using Cx3cr1GFP/+ mice revealed the intimal CX3CR1+ macrophages derived from circulating monocytes. Administration of CCR2 antagonist RS504393 to inhibit monocyte infiltration significantly reduced intimal CX3CR1+ macrophages and subsequently alleviated TAA development in Fbn1C1041G/+ mice. In conclusion, intimal CX3CR1+ macrophages mediated TAA formation through paracrinally causing VSMC inflammation. Targeting intimal CX3CR1+ macrophages would be a promising anti-inflammatory strategy in TAA therapy for MFS.

2024-12-10 | GSE249352 | GEO

Inhibition of the multifunctional homeodomain-interacting protein kinase 2 (HIPK2) alleviates thoracic aortic disease in mice with progressively severe Marfan syndrome

Project description:Inhibition of the multifunctional homeodomain-interacting protein kinase 2 (HIPK2) alleviates thoracic aortic disease in mice with progressively severe Marfan syndrome

| PRJNA608706 | ENA

Inhibition of HIPK2 Alleviates Thoracic Aortic Disease in Mice With Progressively Severe Marfan Syndrome.

Project description:ObjectiveDespite considerable research, the goal of finding nonsurgical remedies against thoracic aortic aneurysm and acute aortic dissection remains elusive. We sought to identify a novel aortic PK (protein kinase) that can be pharmacologically targeted to mitigate aneurysmal disease in a well-established mouse model of early-onset progressively severe Marfan syndrome (MFS).Approach and resultsComputational analyses of transcriptomic data derived from the ascending aorta of MFS mice predicted a probable association between thoracic aortic aneurysm and acute aortic dissection development and the multifunctional, stress-activated HIPK2 (homeodomain-interacting protein kinase 2). Consistent with this prediction, Hipk2 gene inactivation significantly extended the survival of MFS mice by slowing aneurysm growth and delaying transmural rupture. HIPK2 also ranked among the top predicted PKs in computational analyses of DEGs (differentially expressed genes) in the dilated aorta of 3 MFS patients, which strengthened the clinical relevance of the experimental finding. Additional in silico analyses of the human and mouse data sets identified the TGF (transforming growth factor)-β/Smad3 signaling pathway as a potential target of HIPK2 in the MFS aorta. Chronic treatment of MFS mice with an allosteric inhibitor of HIPK2-mediated stimulation of Smad3 signaling validated this prediction by mitigating thoracic aortic aneurysm and acute aortic dissection pathology and partially improving aortic material stiffness.ConclusionsHIPK2 is a previously unrecognized determinant of aneurysmal disease and an attractive new target for antithoracic aortic aneurysm and acute aortic dissection multidrug therapy.

| S-EPMC8530207 | biostudies-literature

A Marfan syndrome gene expression phenotype in cultured skin fibroblasts

Project description:Background: Marfan syndrome (MFS) is a heritable connective tissue disorder caused by mutations in the fibrillin-1 gene. This syndrome constitutes a significant identifiable subtype of aortic aneurysmal disease, accounting for over 5% of ascending and thoracic aortic aneurysms. Results: We used spotted membrane DNA macroarrays to identify genes whose altered expression levels may contribute to the phenotype of the disease. Our analysis of 4132 genes identified a subset with significant expression differences between skin fibroblast cultures from unaffected controls versus cultures from affected individuals with known fibrillin-1 mutations. Subsequently, 10 genes were chosen for validation by quantitative RT-PCR. Conclusions: Differential expression of many of the validated genes was associated with MFS samples when an additional group of unaffected and MFS affected subjects were analyzed (p-value < 3 x 10-6 under the null hypothesis that expression levels in cultured fibroblasts are unaffected by MFS status). An unexpected observation was the range of individual gene expression. In unaffected control subjects, expression ranges exceeding 10 fold were seen in many of the genes selected for qRT-PCR validation. The variation in expression in the MFS affected subjects was even greater. Keywords: disease state comparison; Marfan syndrome; cultured skin fibroblasts

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Project description:Marfan syndrome (MFS) is a connective tissue disorder caused by mutations in the fibrillin-1 (Fbn1) gene. While aortic rupture is the major cause of mortality in MFS, patients also suffer from poorly understood pulmonary complications. Loss of basal nitric oxide (NO) production and vascular integrity are proposed to take part in MFS aortic root disease, yet their contribution to lung complications has yet to be determined. Due to its capacity to potentiate the vasodilatory NO/cyclic guanylate monophosphate signaling pathway, we assessed whether the phosphodiesterase-5 (PDE5) inhibitor sildenafil (SIL) could attenuate aortic root remodelling and emphysema in a mouse model of MFS. Despite increasing NO-dependent vasodilation, SIL unexpectedly elevated mean arterial blood pressure, failed to inhibit MFS aortic root dilation and exacerbated elastic fibrefiber fragmentation. In the lung, early pulmonary artery dilation observed in untreated MFS mice was delayed by SIL treatment, and severe emphysema-like alveolar destruction was prevented. In addition, improvements in select parameters of lung function were documented. Subsequent micro-array analyses showed changes to gene signatures involved in the inflammatory response in MFS lung treated with SIL, without significant downregulation of connective tissue or TGF-β signalling genes. Since PDE5 inhibition leads to improved lung histopathology and function, the effects of SIL against emphysema warrant further investigation in the settings of MFS despite limited efficacy on aortic root remodelling.

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Ang II type 1a receptor in Marfan syndrome

Project description:Using Cdh5-Cre and Sm22-Cre transgenes to characterize the impact of disruption of the angiotensin II type 1a receptor (AT1ar) in vascular endothelial and smooth muscle cells, respectively, of wild type (WT) mice compared to fibrillin-1 hypomorphic mice (Fbn1mgR/mgR mice) that replicate early onset progressively severe Marfan syndrome (MFS) with dissecting thoracic aortic aneurysm (TAA).

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Deregulated MicroRNA and mRNA Expression Profiles in the Peripheral Blood of Patients with Marfan Syndrome (microRNA)

Project description:We performed integrated miRNA and mRNA expression profiling in blood samples of Marfan patients in order to investigate deregulated miRNA and mRNA networks in these patients which could serve as potential diagnostic and prognostic tools for MFS therapy.

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Deregulated MicroRNA and mRNA Expression Profiles in the Peripheral Blood of Patients with Marfan Syndrome (mRNA)

2019-05-22 | GSE110964 | GEO

Subcellular pathways shared by afflicted patients and mutant mice identify a new drug treatment for aortic aneurysm in Marfan syndrome

Project description:We analyzed differentially expressed genes in smooth muscle cells derived from the thoracic aorta of Marfan Syndrome (MFS) patients and control subjects to identify cell biological mechanisms contributing to thoracic aoritc aneurysm (TAA) development and rupture. These mechanisms were used to identify a potential drug treatment to mitigate TAA progression. We analyzed differentially expressed genes in whole aorta of P16 MFS mice vs WT mice to identify cell biological mechanisms contributing to thoracic aoritc aneurysm (TAA) development and rupture. These mechanisms were used to identify baclofen as a potential drug treatment to mitigate TAA progression. The effect of baclofen on gene expression in WT and MFS was documented in P60 mice that received treatment since P16.

2019-11-18 | GSE128101 | GEO

Dissecting aortic aneurysm in Marfan syndrome is associated with losartan-sensitive transcriptomic modulation of aortic cells

Project description:To improve our limited understanding of the pathogenesis of thoracic aortic aneurysm (TAA) leading to acute aortic dissection, we used single-cell RNA sequencing to profile disease-relevant transcriptomic changes of aortic cell populations in a well-characterized mouse model of the most commonly diagnosed form of Marfan syndrome (MFS). As result,MFSmod were identified only in the aorta of Fbn1mgR/mgR mice. In situ hybridizations of diagnostic transcripts located MFSmod cells to the intima of Fbn1mgR/mgR aortas. Consistent with angiotensin II type I receptor (At1r) contribution to TAA development, MFSmod cells were absent in the aorta of Fbn1mgR/mgR mice treated with the At1r antagonist losartan. Altogether, our findings indicate that a discrete dynamic alteration of aortic cell identity is associated with dissecting TAA in MFS mice and increased risk of aortic dissection in MFS patients.

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