title: Targeting the calpain/calpastatin system as a new strategy to prevent cardiovascular remodeling in angiotensin II-induced hypertension.
abstract: In hypertension, angiotensin (Ang) II is a critical mediator of cardiovascular remodeling, whose prominent features include myocardial and vascular media hypertrophy, perivascular inflammation, and fibrosis. The signaling pathways responsible for these alterations are not completely understood. Here, we investigated the importance of calpains, calcium-dependent cysteine proteases. We generated transgenic mice constitutively expressing high levels of calpastatin, a calpain-specific inhibitor. Chronic infusion of Ang II led to similar increases in systolic blood pressure in wild-type and transgenic mice. In contrast, compared with wild-type mice, transgenic mice displayed a marked blunting of Ang II-induced hypertrophy of left ventricle. Ang II-dependent vascular remodeling, ie, media hypertrophy and perivascular inflammation and fibrosis, was also limited in both large arteries (aorta) and small kidney arteries from transgenic mice as compared with wild type. In vitro experiments using vascular smooth muscle cells showed that calpastatin transgene expression blunted calpain activation by Ang II through epidermal growth factor receptor transactivation. In vivo and in vitro models of inflammation showed that impaired recruitment of mononuclear cells in transgenic mice was attributable to a decrease in both the release of and the chemotactic response to monocyte chemoattractant protein-1. Finally, results from collagen synthesis assay and zymography suggested that limited fibrogenesis was attributable to a decrease in collagen deposition rather than an increase in collagen degradation. These results indicate a critical role for calpains as downstream mediators in Ang II-induced cardiovascular remodeling and, thus, highlight an attractive therapeutic target.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, U702, Paris, France.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Letavernier
authors.forename: Joëlle
authors.initials: J
authors.lastname: Perez
authors.forename: Agnès
authors.initials: A
authors.lastname: Bellocq
authors.forename: Laurent
authors.initials: L
authors.lastname: Mesnard
authors.forename: Alexandre
authors.initials: A
authors.lastname: de Castro Keller
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Haymann
authors.forename: Laurent
authors.initials: L
authors.lastname: Baud
mesh_terms: D000804:Angiotensin II / Q000008:administration & dosage; D000818:Animals; D001011:Aorta / Q000201:enzymology / Q000473:pathology; D001794:Blood Pressure; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D002154:Calpain / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D005355:Fibrosis; D015316:Genetic Therapy / Q000379:methods; D006973:Hypertension / Q000139:chemically induced / Q000150:complications* / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy; D006984:Hypertrophy; D017379:Hypertrophy, Left Ventricular / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D007249:Inflammation / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D015918:Infusion Pumps, Implantable; D051379:Mice; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000473:pathology; D009206:Myocardium / Q000201:enzymology / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000378:metabolism; D012077:Renal Artery / Q000201:enzymology / Q000473:pathology; D013997:Time Factors; D020257:Ventricular Remodeling
chemical_list: D002135:Calcium-Binding Proteins; D015853:Cysteine Proteinase Inhibitors; D016328:NF-kappa B; D050778:NFATC Transcription Factors; D000804:Angiotensin II; C033668:calpastatin; D002154:Calpain