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RNA-seq of the aorta from sST2-knockout mice in angiotensin II-induced aortic disease model

ABSTRACT: Soluble ST2 (sST2) is a well-established prognostic biomarker for aortic aneurysm (AA); however, its direct contribution to AA pathogenesis remains obscure. While traditionally characterized as a decoy receptor for IL-33, whether sST2 exerts independent biological functions in vascular remodeling is unknown. Here, we demonstrate that elevated sST2 levels actively drive AA progression. Using gain-and loss-of-function ApoE-/- mouse models infused with Angiotensin II (Ang II), we found that sST2 overexpression significantly exacerbated aortic rupture, dissection, and mortality, whereas sST2 deficiency conferred robust protection against aneurysm formation. Mechanistically, transcriptomic profiling and molecular validation revealed that sST2 triggers phenotypic switching, inflammation, and extracellular matrix degradation in vascular smooth muscle cells (VSMCs). We identified a novel, IL-33-independent signaling axis wherein sST2 rapidly activates STAT3 phosphorylation, subsequently upregulating the expression and secretion of the chemokine CXCL1 from VSMCs. This sST2-STAT3-CXCL1 axis orchestrates medial degeneration. Furthermore, pharmacological inhibition of STAT3 using Cryptotanshinone (CPT) effectively blocked the sST2-induced upregulation of CXCL1 and reversed maladaptive aortic remodeling in vivo and in vitro. Collectively, our findings challenge the canonical view of sST2 as solely a decoy receptor, uncovering a distinct pathogenic role in AA. Targeting the sST2-STAT3-CXCL1 axis represents a promising therapeutic strategy, with Cryptotanshinone emerging as a potential candidate for clinical intervention.

ORGANISM(S): Mus musculus

PROVIDER: GSE318210 | GEO | 2026/02/04

REPOSITORIES: GEO

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RNA-seq of human aortic smooth muscle cells treated with recombinant sST2 and angiotensin II

Project description:Soluble ST2 (sST2) is a well-established prognostic biomarker for aortic aneurysm (AA); however, its direct contribution to AA pathogenesis remains obscure. While traditionally characterized as a decoy receptor for IL-33, whether sST2 exerts independent biological functions in vascular remodeling is unknown. Here, we demonstrate that elevated sST2 levels actively drive AA progression. Using gain-and loss-of-function ApoE-/- mouse models infused with Angiotensin II (Ang II), we found that sST2 overexpression significantly exacerbated aortic rupture, dissection, and mortality, whereas sST2 deficiency conferred robust protection against aneurysm formation. Mechanistically, transcriptomic profiling and molecular validation revealed that sST2 triggers phenotypic switching, inflammation, and extracellular matrix degradation in vascular smooth muscle cells (VSMCs). We identified a novel, IL-33-independent signaling axis wherein sST2 rapidly activates STAT3 phosphorylation, subsequently upregulating the expression and secretion of the chemokine CXCL1 from VSMCs. This sST2-STAT3-CXCL1 axis orchestrates medial degeneration. Furthermore, pharmacological inhibition of STAT3 using Cryptotanshinone (CPT) effectively blocked the sST2-induced upregulation of CXCL1 and reversed maladaptive aortic remodeling in vivo and in vitro. Collectively, our findings challenge the canonical view of sST2 as solely a decoy receptor, uncovering a distinct pathogenic role in AA. Targeting the sST2-STAT3-CXCL1 axis represents a promising therapeutic strategy, with Cryptotanshinone emerging as a potential candidate for clinical intervention.

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