Anxa1 in smooth muscle cells protects against acute aortic dissection

Abstract

Aims Acute aortic dissection (AAD) is a life-threatening disease with high morbidity and mortality. Previous studies have showed that vascular smooth muscle cell (VSMC) phenotype switching modulates vascular function and AAD progression. However, whether an endogenous signaling system that protects AAD progression exists, remains unknown. Our aim is to investigate the role of Anxa1 in VSMC phenotype switching and the pathogenesis of AAD. Methods and Results We first assessed Anxa1 expression levels by immunohistochemical staining in control aorta and AAD tissue from mice. A strong increase of Anxa1 expression was seen in the mouse AAD tissues. In line with these findings, micro-CT scan results indicated that Anxa1 plays a role in the development of AAD in our murine model, with systemic deficiency of Anxa1 markedly progressing AAD. Conversely, administration of Anxa1 mimetic peptide, Ac2-26, rescued the AAD phenotype in Anxa1-/- mice. Transcriptomic studies revealed a novel role for Anxa1 in VSMC phenotype switching, with Anxa1 deficiency triggering the synthetic phenotype of VSMCs via down-regulation of the JunB/MYL9 pathway. The resultant VSMC synthetic phenotype rendered elevated inflammation and enhanced matrix metalloproteinases (MMPs) production, leading to augmented elastin degradation. VSMC-restricted deficiency of Anxa1 in mice phenocopied VSMC phenotype switching and the consequent exacerbation of AAD. Finally, our studies in human AAD aortic specimens recapitulated key findings in murine AAD, specifically that the decrease of Anxa1 is associated with VSMC phenotype switch, heightened inflammation, and enhanced MMP production in human aortas. Conclusions Our findings demonstrated that Anxa1 is a novel endogenous defender that prevents acute aortic dissection by inhibiting vascular smooth muscle cell phenotype switching, suggesting that Anxa1 signaling may be a potential target for AAD pharmacological therapy. Translational Perspective Our studies herein may lead to a paradigm shift for pharmacologic therapy towards acute aortic dissection. Through careful examination of the pathological changes that occur during AAD onset in experimental animal models, we demonstrated that VSMC phenotype switching plays a critical role in the development of AAD. Inhibition of VSMC phenotype switching and its attendant impacts on aortic function may be a viable approach for future treatment. Toward that end, our studies highlighted the protective benefit of Anxa1 and its mimetic peptide Ac2-26 in AAD through prevention of the switching of VSMC to a synthetic phenotype.

Vascular Smooth Muscle Cells Phenotypic Switching in Cardiovascular Diseases

“…Anxa1 blocks the production of a synthesis phenotype of VSMCs by downregulating the JunB/MYL9 pathway, which leads to increased inflammation and enhanced matrix metalloproteinase (MMP) production, resulting in increased elastin degradation and subsequent worsening of acute aortic dissection (AAD) [ 75 ]. It was revealed that 5’-tiRNA-Cys-GCA was decreased in human and mouse aortic dissection models, and 5’-tiRNA-Cys-GCA overexpression inhibited the proliferation and migration of vascular smooth muscle cells through STAT4, upregulated contractile markers, reduced the incidence of angiotensin II and β-aminopropionitrile-induced aortic dissection (AD) in mice and prevented its deterioration [ 76 ].…”

Annexins and cardiovascular diseases: Beyond membrane trafficking and repair

“…Thus, AnxA1 deficiency in SMCs aggravates acute aortic dissection (AAD) in mice (Zhou et al, 2022). In addition, Ac2-26 administration decreased AAD incidence in AnxA1 −/− mice decreasing SMCs phenotypic switching to a secretory phenotype (Zhou et al, 2022). Taken together, in vivo studies reveal that administration of AnxA1 or derived peptides could serve to prevent pathological vascular remodeling.…”

“…AnxA1 plays an important role in maintaining SMCs homeostasis and protection against acute aortic dissection. Thus, AnxA1 deficiency in SMCs aggravates acute aortic dissection (AAD) in mice (Zhou et al, 2022). In addition, Ac2-26 administration decreased AAD incidence in AnxA1 −/− mice decreasing SMCs phenotypic switching to a secretory phenotype (Zhou et al, 2022).…”

Therapeutic potential for targeting Annexin A1 in fibrotic diseases

“… 56 Zhao et al recently showed that Annexin A1 mitigated myocardial ischemia-reperfusion injury by activating signal transducer and activator of transcription 3 (STAT3) signaling pathway to suppress polymorphonuclear neutrophil infiltration and myeloperoxidase activity. 57 Purvis et al elegantly suggested that recombinant human Annexin A1 may represent a novel candidate for type-2 diabetes and/or its complications via mediating the RhoA activity, which restores insulin receptor substrate 1 (IRS1) signal transduction. 58 As the predominant strategy that treat fibrosis in various organs, anti-inflammatory response gathers multitudinous attention.…”