title: Calpain inhibition attenuates angiotensin II-induced abdominal aortic aneurysms and atherosclerosis in low-density lipoprotein receptor-deficient mice.
abstract: Chronic infusion of angiotensin II (AngII) augments atherosclerosis and abdominal aortic aneurysm (AAA) formation in hypercholesterolemic mice. AngII-induced AAAs are associated with medial macrophage accumulation and matrix metalloproteinase (MMP) activation. Inhibition of calpain, a calcium-activated neutral cysteine protease, by overexpression of its endogenous inhibitor, calpastatin, attenuates AngII-induced leukocyte infiltration, perivascular inflammation, and MMP activation in mice. The purpose of this study was to define whether pharmacological inhibition of calpain influences AngII-induced AAAs in hypercholesterolemic mice. Male low-density lipoprotein receptor-/- mice were fed a fat-enriched diet and administered with either vehicle or a calpain-specific inhibitor, BDA-410 (30 mg/kg per day) for 5 weeks. After 1 week of feeding, mice were infused with AngII (1000 ng/kg per minute) for 4 weeks. AngII-infusion profoundly increased aortic calpain protein and activity. BDA-410 administration had no effect on plasma cholesterol concentrations or AngII-increased systolic blood pressure. Calpain inhibition significantly attenuated AngII-induced AAA formation and atherosclerosis development. BDA-410 administration attenuated activation of MMP12, proinflammatory cytokines (IL-6, monocyte chemoattractant protein-1), and macrophage infiltration into the aorta. BDA-410 administration significantly attenuated thioglycolate-elicited macrophage accumulation in the peritoneal cavity. We conclude that calpain inhibition using BDA-410 attenuated AngII-induced AAA formation and atherosclerosis development in low-density lipoprotein receptor-/- mice.
authors.affiliation: Saha Cardiovascular Research Center, University of Kentucky, Lexington, KY 40536-0509, USA. venkat.subramanian@uky.edu
authors.forename: Venkateswaran
authors.initials: V
authors.lastname: Subramanian
authors.forename: Haruhito A
authors.initials: HA
authors.lastname: Uchida
authors.forename: Talha
authors.initials: T
authors.lastname: Ijaz
authors.forename: Jessica J
authors.initials: JJ
authors.lastname: Moorleghen
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Howatt
authors.forename: Anju
authors.initials: A
authors.lastname: Balakrishnan
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D017544:Aortic Aneurysm, Abdominal / Q000201:enzymology / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D050197:Atherosclerosis / Q000201:enzymology / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D015153:Blotting, Western; D002154:Calpain / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D006937:Hypercholesterolemia / Q000150:complications / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011973:Receptors, LDL / Q000172:deficiency* / Q000235:genetics; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D015853:Cysteine Proteinase Inhibitors; 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