CARMA3 Deficiency Aggravates Angiotensin II-Induced Abdominal Aortic Aneurysm Development Interacting Between Endoplasmic Reticulum and Mitochondria

Background: Abdominal aortic aneurysm (AAA) is life threatening and associated with vascular walls' chronic inflammation. However, a detailed understanding of the underlying mechanisms is yet to be elucidated. CARMA3 assembles the CARMA3-BCL10-MALT1 (CBM) complex in inflammatory diseases and is proven to mediate angiotensin II (Ang II) response to inflammatory signals by modulating DNA damage-induced cell pyroptosis. In addition, interaction between endoplasmic reticulum (ER) stress and mitochondrial damage is one of the main causes of cell pyroptosis. Methods: Male wild type (WT) or CARMA3-/-mice aged 8 to 10 weeks were subcutaneously implanted with osmotic minipumps, delivering saline or Ang II at the rate of 1 mg/kg/min for 1, 2, and 4 weeks. Results: We discovered that CARMA3 knockout promoted formation of AAA and prominently increased diameter and severity of the mice abdominal aorta infused with Ang II. Moreover, a significant increase in the excretion of inflammatory cytokines, expression levels of matrix metalloproteinases (MMPs) and cell death was found in the aneurysmal aortic wall of CARMA3-/-mice infused with Ang II compared with WT mice. Further studies found that the degree of ER stress and mitochondrial damage in the abdominal aorta of CARMA3-/-mice was more severe than that in WT mice. Mechanistically, CARMA3 defi- ciency exacerbates the interaction between ER stress and mitochondrial damage by activating the p38MAPK pathway, ultimately contributing to the pyroptosis of vascular smooth muscle cells (VSMCs). Conclusions: CARMA3 appears to play a key role in AAA formation and might be a potential target for therapeutic interventions of AAA.