Abstract
Background and ObjectiveRecently, we demonstrated that angiotensin II (AngII)-infusion profoundly increased both aortic protein and activity of calpains, calcium-activated cysteine proteases, in mice. In addition, pharmacological inhibition of calpain attenuated AngII-induced abdominal aortic aneurysm (AA) in mice. Recent studies have shown that AngII infusion into mice leads to aneurysmal formation localized to the ascending aorta. However, the precise functional contribution of calpain isoforms (-1 or -2) in AngII-induced abdominal AA formation is not known. Similarly, a functional role of calpain in AngII-induced ascending AA remains to be defined. Using BDA-410, an inhibitor of calpains, and calpain-1 genetic deficient mice, we examined the relative contribution of calpain isoforms in AngII-induced ascending and abdominal AA development.Methodology/ResultsTo investigate the relative contribution of calpain-1 and -2 in development of AngII-induced AAs, male LDLr −/− mice that were either calpain-1 +/+ or −/− were fed a saturated fat-enriched diet and infused with AngII (1,000 ng/kg/min) for 4 weeks. Calpain-1 deficiency had no significant effect on body weight or blood pressure during AngII infusion. Moreover, calpain-1 deficiency showed no discernible effects on AngII-induced ascending and abdominal AAs. Interestingly, AngII infusion induced increased expression of calpain-2 protein, thus compensating for total calpain activity in aortas of calpain-1 deficient mice. Oral administration of BDA-410, a calpain inhibitor, along with AngII-infusion significantly attenuated AngII-induced ascending and abdominal AA formation in both calpain-1 +/+ and −/− mice as compared to vehicle administered mice. Furthermore, BDA-410 administration attenuated AngII-induced aortic medial hypertrophy and macrophage accumulation. Western blot and immunostaining analyses revealed BDA-410 administration attenuated AngII-induced C-terminal fragmentation of filamin A, an actin binding cytoskeletal protein in aorta.ConclusionCalpain-2 compensates for loss of calpain-1, and both calpain isoforms are involved in AngII-induced aortic aneurysm formation in mice.
Highlights
Ascending and abdominal aortic aneurysms (AAs) are two major common aortic diseases that have highly distinct pathologies, and mediated by different etiologies [1]
Calpain-2 compensates for loss of calpain-1, and both calpain isoforms are involved in angiotensin II (AngII)-induced aortic aneurysm formation in mice
Calpains are Present in AngII-induced Abdominal AAs Immunostaining using calpain-1, -2 and cell specific antibodies were performed on AngII-induced abdominal AA sections to examine the distribution and localization of calpains in abdominal AAs
Summary
Ascending and abdominal aortic aneurysms (AAs) are two major common aortic diseases that have highly distinct pathologies, and mediated by different etiologies [1]. It was recognized that AngII-infusion leads to aneurysmal formation localized to the ascending aorta [10]. AngII infusion develops both ascending and abdominal AAs in the same mouse model, the underlying pathologies are clearly distinct between the two forms. AngII-induced ascending AAs are characterized with macrophage accumulation throughout the aortic circumference, predominantly on the adventitial side of the aorta [10]. Systemic deficiency of angiotensin II type 1a (AT1a) receptor completely ablates the development of AngII-induced ascending and abdominal AAs in mice [12,13]. Recent studies have shown that AngII infusion into mice leads to aneurysmal formation localized to the ascending aorta. Using BDA-410, an inhibitor of calpains, and calpain-1 genetic deficient mice, we examined the relative contribution of calpain isoforms in AngII-induced ascending and abdominal AA development
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