# Adipocyte Calpain‐2 Deficiency Reduces Obesity‐Accelerated Abdominal Aortic Aneurysm Formation in Mice

## TL;DR

Deleting calpain-2 in fat cells of mice reduces the risk of obesity-related abdominal aortic aneurysms by decreasing inflammation and tissue damage.

## Contribution

The study identifies adipocyte-specific calpain-2 as a novel therapeutic target for obesity-accelerated aneurysms.

## Key findings

- Adipocyte-specific calpain-2 deletion significantly suppressed AngII-induced AAA formation in obese mice.
- Calpain-2 deficiency reduced aortic medial elastin fragmentation and periaortic leukocyte accumulation.
- Targeted inhibition of calpain-2 may offer a new treatment for obesity-related aneurysms.

## Abstract

Abdominal adiposity is associated with increased risk of abdominal aortic aneurysm (AAA) development. Calpains are non‐lysosomal calcium‐dependent cysteine proteases that are highly expressed in human and experimental AAAs. Using a pharmacological inhibitor and genetically deficient mice, we previously demonstrated that calpain‐2 (a major ubiquitous isoform) deficiency mitigated angiotensin II (AngII)‐induced AAA formation in hypercholesterolemic mice. In addition, we also demonstrated that calpain inhibition strongly suppressed adipose tissue inflammation in obese mice. Here, we evaluated the contribution of adipocyte‐specific calpain‐2 on obesity‐accelerated AAA in mice. Calpain‐2 protein is highly expressed in the periaortic adipose tissue (PAAT) of AngII‐induced AAAs in obese mice. To determine the relative contribution of calpain‐2 in obesity‐accelerated AAA development, calpain‐2 floxed mice were bred to mice with a tamoxifen‐inducible form of Cre under control of either the ubiquitous promoter, chicken β‐actin, or adipocyte‐specific promoter, Adipoq. Ubiquitous or adipocyte‐specific depletion of calpain‐2 in mice significantly suppressed Ang II–induced AAA formation in obese mice. In addition, calpain‐2 depletion reduced the incidence of AngII‐induced AAAs in mice. Furthermore, calpain‐2 deficiency prevented AngII‐induced aortic medial elastin fragmentation, adventitial collagen disruption, and periaortic leukocytic accumulation. These results suggest that adipocyte‐derived calpain‐2 plays a critical role in AngII‐induced AAA development in diet‐induced obese mice.

Adipocyte‐specific deletion of calpain‐2 in mice decreases obesity‐accelerated abdominal aortic aneurysm formation, which is associated with reduced aortic medial elastin fragmentation and periaortic adipose tissue leukocyte accumulation. Targeted inhibition of calpain‐2 may offer a new therapeutic target to reduce obesity‐accelerated abdominal aortic aneurysms.