Gasdermin D Deficiency in Vascular Smooth Muscle Cells Ameliorates Abdominal Aortic Aneurysm Through Reducing Putrescine Synthesis

Abstract

Abdominal aortic aneurysm (AAA) is a common vascular disease associated with significant phenotypic alterations in vascular smooth muscle cells (VSMCs). Gasdermin D (GSDMD) is a pore‐forming effector of pyroptosis. In this study, the role of VSMC‐specific GSDMD in the phenotypic alteration of VSMCs and AAA formation is determined. Single‐cell transcriptome analyses reveal Gsdmd upregulation in aortic VSMCs in angiotensin (Ang) II‐induced AAA. VSMC‐specific Gsdmd deletion ameliorates Ang II‐induced AAA in apolipoprotein E (ApoE)−/− mice. Using untargeted metabolomic analysis, it is found that putrescine is significantly reduced in the plasma and aortic tissues of VSMC‐specific GSDMD deficient mice. High putrescine levels trigger a pro‐inflammatory phenotype in VSMCs and increase susceptibility to Ang II‐induced AAA formation in mice. In a population‐based study, a high level of putrescine in plasma is associated with the risk of AAA (p < 2.2 × 10−16), consistent with the animal data. Mechanistically, GSDMD enhances endoplasmic reticulum stress‐C/EBP homologous protein (CHOP) signaling, which in turn promotes the expression of ornithine decarboxylase 1 (ODC1), the enzyme responsible for increased putrescine levels. Treatment with the ODC1 inhibitor, difluoromethylornithine, reduces AAA formation in Ang II‐infused ApoE−/− mice. The findings suggest that putrescine is a potential biomarker and target for AAA treatment.

Maresin‐1 ameliorates hypertensive vascular remodeling through its receptor LGR6

“…32,33 GSDMD deficiency in VSMCs ameliorates vascular remodeling in abdominal aortic aneurysm. 34 Our study demonstrated that MaR1 could inhabit VSMC differentiation and pyroptosis induction, thereby reversing hypertensive vascular remodeling.…”

“…Furthermore, hypertensive stress also activates inflammasome and triggers pyroptosis in VSMCs, which contributes to vascular remodeling 32,33 . GSDMD deficiency in VSMCs ameliorates vascular remodeling in abdominal aortic aneurysm 34 . Our study demonstrated that MaR1 could inhabit VSMC differentiation and pyroptosis induction, thereby reversing hypertensive vascular remodeling.…”

The gasdermin family: emerging therapeutic targets in diseases

“… 437 , 438 Gao et al demonstrated that vascular smooth muscle cell (VSMC)-specific GSDMD defects reduced the incidence of AAA in a mouse model. 439 Mechanistically, GSDMD enhances ER stress-CHOP signaling, which subsequently stimulates the expression of ornithine decarboxylase 1 (ODC1), an enzyme that mediates an increase in putrescine levels. High putrescine triggers a pro-inflammatory switch in VSMCs and increases the vulnerability of mice to the development of Ang II-induced AAA.…”

The Role of Gasdermin-D-Mediated Pyroptosis in Organ Injury and Its Therapeutic Implications

“…GSDMD specific deficiency in vascular smooth muscle cells alleviates abdominal aortic aneurysm (AAA) by reducing putrescine compound levels in the aorta. 24 Inhibiting the synthesis of putrescine with difluoromethylornithine (DMFO), a compound in a clinical trial for Neuroblastoma, results in the prevention of AAA development. Thus, DMFO could be a potential drug for AAA treatment with few side effects ( Table 1 ).…”

“…Thus, DMFO could be a potential drug for AAA treatment with few side effects ( Table 1 ). 24 GSDMD is activated in macrophages and vascular smooth muscle cells in human plaques, which exacerbates atherogenesis; thus, inhibition of GSDMD and pyroptosis in atherosclerosis can be a potential therapeutic target. 72 …”