title: Calpain-2 compensation promotes angiotensin II-induced ascending and abdominal aortic aneurysms in calpain-1 deficient mice.
abstract: OBJECTIVE
  Recently, 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.
  
  
  RESULTS
  To 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.
  
  
  CONCLUSIONS
  Calpain-2 compensates for loss of calpain-1, and both calpain isoforms are involved in AngII-induced aortic aneurysm formation in mice.
authors: Saha Cardiovascular Research Center, University of Kentucky, Lexington, Kentucky, United States of America. venkat.subramanian@uky.edu
authors: Venkateswaran
authors: V
authors: Subramanian
authors: Jessica J
authors: JJ
authors: Moorleghen
authors: Anju
authors: A
authors: Balakrishnan
authors: Deborah A
authors: DA
authors: Howatt
authors: Athar H
authors: AH
authors: Chishti
authors: Haruhito A
authors: HA
authors: Uchida
mesh_terms: D000804:Angiotensin II / Q000008:administration & dosage / Q000378:metabolism*; D000818:Animals; D001011:Aorta / Q000378:metabolism* / Q000473:pathology; D001012:Aorta, Abdominal / Q000378:metabolism* / Q000473:pathology; D017544:Aortic Aneurysm, Abdominal / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002154:Calpain / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D059305:Diet, High-Fat; D004791:Enzyme Inhibitors / Q000494:pharmacology; D064448:Filamins / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D015398:Signal Transduction; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D064448:Filamins; C529499:FlnA protein, mouse; C572617:N-1-(hydroxy(3-oxo-2-phenyl-1-cyclopropen-1-yl)methyl)-2-methylpropyl-2-benzenesulfonylamino-4-methylpentanamide; D011973:Receptors, LDL; D013449:Sulfonamides; D000804:Angiotensin II; D002154:Calpain; C112682:Capn1 protein, mouse; C570925:Capn2 protein, mouse
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