MMP19 in vascular smooth muscle cells protects against thoracic aortic aneurysm and dissection via the MMP19/Aggrecan/Wnt/β-Catenin axis
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ABSTRACT:
PROVIDER: PRJNA1214779 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR32094571_1.fastq.gz | Fastqsanger.gz | |||
| SRR32094571_2.fastq.gz | Fastqsanger.gz | |||
| SRR32094572_1.fastq.gz | Fastqsanger.gz | |||
| SRR32094572_2.fastq.gz | Fastqsanger.gz | |||
| SRR32094573_1.fastq.gz | Fastqsanger.gz |
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Project description:Background: Thoracic aortic aneurysm and dissection (TAAD) is a life-threatening cardiovascular event characterized by high mortality rates. Previous studies have shown that matrix metalloproteinases 19 (MMP19) was involved in TAAD formation, while the detailed role of MMP19 in TAAD pathogenesis and underlying mechanism remain unclear. Methods: To investigate the role of MMP19 in the progression of TAAD, we generated global Mmp19 knockout mice, as well as VSMCs (vascular smooth muscle cells)-specific Mmp19 knockdown mice, and established a BAPN-induced TAAD model. To elucidate the signaling pathways modulated by Aggrecan, we employed an adeno-associated virus serotype 9 (AAV9) vector encoding Acan short hairpin RNA (shRNA) for VSMC-specific knockdown of Acan. Ultimately, we injected an AAV vector encoding VSMC-specific Mmp19 into BAPN-induced TAAD mice to assess whether MMP19 can mitigate the development of TAAD. Results: Our findings revealed elevated mRNA and protein levels of MMP19 in the aortas of both TAAD mice and patients. The systemic ablation of Mmp19, as well as VSMC-specific Mmp19 knockdown, significantly exacerbated BAPN-induced progressive TAAD, and TAAD-related cardiovascular remodeling. Mmp19 deficiency resulted in the accumulation of Acan, but not Vcan, within the aorta, driving the phenotypic switch of VSMCs from contractile to synthetic state through activting Wnt/β-catenin signaling pathway. The selective inhibitor of Wnt/β-catenin signaling, MASB, was effective in reversing the dedifferentiation of VSMCs induced by aggrecan accumulation. Notably, the specific knockdown of Acan in VSMCs restored the contractile phenotype of VSMCs and inhibited Wnt/β-catenin signaling, thereby alleviating BAPN-induced TAAD in Mmp19-/- mice. Additionally, VSMC-specific complementation of MMP19 also alleviated the progressive TAAD phenotype in Mmp19-/- mice. Conclusions: The study underscores that MMP19 deficiency exacerbates TAAD by promoting Acan aggregation and destroying the homeostasis of VSMCs by activating Wnt/β-catenin signaling pathway. These results posit MMP19 as a promising novel therapeutic target for TAAD intervention.
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Project description:Recent studies show that hyperactivation of mTOR signaling plays a causal role in the development of thoracic aortic aneurysm (TAA) and dissection (AAD). Modulation of Protein phosphatase 2A (PP2A) activity has been shown to be of significant therapeutic value. In light of the effects that PP2A can exert on mTOR pathway, we hypothesized that PP2A activation by small molecule activators of PP2A (SMAPs) could mitigate AA progression in Marfan Syndrome (MFS).
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Project description:Genetic factors are fundamental in the etiology of thoracic aortic aneurysm and dissection (TAAD), but the genetic cause is detected in only about 30% of cases. To define unreported TAAD-associated sequence variants, exome and gene panel sequencing was performed in 323 patients. We identified heterozygous CDKL1 variants [c.427T>C p.(Cys143Arg), c.617C>T p.(Ser206Leu), and c.404C>T p.(Thr135Met)] in 6 patients from 3 families with TAAD-spectrum disorders. CDKL1 encodes a protein kinase involved in ciliary biology. Amino acid substitutions were predicted to affect CDKL1 catalytic activity or protein binding properties. CDKL1 was expressed in vascular smooth muscle cells in normal and diseased human aortic wall tissue. Cdkl1 knockdown and transient knockout in zebrafish resulted in intersomitic vessel (ISV) malformations and aortic dilation. Co-injection of human CDKL1wildtype, but not CDKL1Cys143Arg and CDKL1Ser206Leu RNA, rescued ISV malformations. All variants affected CDKL1 kinase function and profiling data, and altered protein-protein binding properties, particularily with ciliary transport molecules. Expression of CDKL1 variants in heterologeous cells interfered with cilia formation and length, CDKL1 localization, and p38-MAPK and Vegf signaling. Our data suggest a role of CDKL1 variants in the pathogenesis of TAAD-spectrum disorders. The association between primary cilia dysregulation and TAAD expands our knowledge of the underlying molecular pathophysiology.
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Project description:Descending thoracic aortic aneurysms and dissections can go undetected until severe and catastrophic, and few clinical indices exist to screen for aneurysms or predict their risk of dissection or rupture. This study generated a plasma proteomic dataset from 150 patients with descending thoracic aortic disease and 52 controls to identify proteomic signatures capable of differentiating descending thoracic aortic disease from non-disease controls, as well as between cases with aneurysm versus descending ‘type B’ dissection. Of the 1,468 peptides and 195 proteins quantified across all samples, 853 peptides and 99 proteins were quantitatively different between disease and control patients (BH adjusted p-value < 0.01 from t-tests). Supervised machine learning (ML) methods were used to classify disease from control and aneurysm from descending dissection cases. The highest precision-recall area under the curve (PR AUC) was achieved on the held-out test set using significantly different proteins between disease and control patients (PR AUC 0.99), followed by input of significant peptides (PR AUC 0.96). Despite no statistically significant proteins between aneurysm and dissection cases, use of all proteins was able to modestly classify between the two disease states (PR AUC 0.77). To overcome correlation in the proteins and enable biological pathway analysis, a disease versus control classifier was optimized using only seven unique protein clusters, which achieved comparable performance to models trained on all/significant proteins (accuracy 0.88, F1-score 0.78, PR AUC 0.90). Model interpretation with permutation importance revealed that proteins in the most important clusters for differentiating disease and control function in coagulation, protein-lipid complex remodeling, and acute inflammatory response.
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Project description:Aortic aneurysm and dissection (AAD) is a life-threatening disease without effective pharmacological treatments. The progressive loss of vascular smooth muscle cells (VSMCs) is the fundamental pathophysiological basis for AAD, but the underlying mechanisms are largely unknown. Sirtuin 6 (SIRT6), a class III histone deacetylase, is critical for maintenance of VSMC homeostasis and consequent prevention of vascular remodeling-related diseases. However, its role in AAD development requires further investigation. Here, we show that SIRT6 expression was significantly reduced in VSMCs of the thoracic aorta in AAD patients. Sirt6 deficiency in VSMCs dramatically accelerated angiotensin Ⅱ (Ang Ⅱ) infusion-induced AAD formation and rupture even without an Apoe-deficient background. In vitro studies demonstrated that Sirt6 deficiency led to mitochondrial dysfunction and accelerated VSMC senescence. Mechanistically, SIRT6 could bind and deacetylate NRF2, a key transcription factor for mitochondrial biogenesis, however, Sirt6 deficiency inhibited NRF2 and reduced mRNAs encoding mitochondrial complex. Notably, MDL-811, a newly developed small-molecule SIRT6 agonist, effectively reversed Ang Ⅱ-induced mitochondrial dysfunctions in human aortic smooth muscle cells. More importantly, MDL-811 also mitigated AAD progression in mice. These findings suggest that SIRT6 plays a protective role in AAD development and targeting SIRT6 with small-molecule activators such as MDL-811 could represent a promising therapeutic strategy for AAD.
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