Abstract 700: Adipocyte-Specific Calpain-2 Deficiency Attenuates Obesity-accelerated Abdominal Aortic Aneurysms in Mice

Background and Objective: Recent clinical studies demonstrated that 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 identified that calpain-2 (a major ubiquitous isoform) plays a critical role in Angiotensin II (AngII)-induced AAA formation in obese mice. In addition, we demonstrated that calpain inhibition strongly suppressed adipose tissue inflammation in obese mice. The purpose of this study was to determine the role of adipocyte-specific calpain-2 on obesity-accelerated AAA. Methods and Results: Calpain-2 floxed mice that were hemizygous for Adiponectin Cre (Cre+/0) were produced by breeding male Cre+/0 to female calpain-2 floxed mice. Littermates that were homozygous for the floxed calpain-2 gene, but without the Cre transgene (Cre0/0), were used as control mice. Western blot analyses showed that calpain-2 protein is depleted in various fat tissues including periaortic adipose, from Cre+/0 mice, while not influencing abundance in aorta and other tissues. Male Cre+/0 and Cre0/0 mice were fed a high fat diet (60% Kcal) for 20 weeks. After 16 weeks of diet feeding, mice (n=20-22) were infused with either saline or AngII (1,000 ng/kg/min) by osmotic minipumps for 4 weeks. Depletion of calpain-2 in adipocytes had no effect on high fat diet-induced body weight gain, fat mass, glucose and insulin tolerance. Interestingly, adipocyte-specific calpain-2 depletion significantly attenuated AngII-induced expansion of ex-vivo maximal diameter of abdominal aortas in obese mice (Saline- Cre0/0: 0.95 ± 0.03; Cre+/0: 0.98 ± 0.02 mm; AngII - Cre0/0: 1.95 ± 0.20; Cre+/0: 1.25 ± 0.08 mm P<0.001). In addition, calpain-2 depletion also reduced the incidence of AngII-induced AAAs in mice (Cre0/0: 76% versus Cre+/0: 27%). Conclusion: These findings suggest that adipocyte-derived calpain-2 plays a critical role in AngII-induced AAA development in diet-induced obese mice.