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(Circulation Research. 2008;102:720.)
© 2008 American Heart Association, Inc.

Integrative Physiology

Targeting the Calpain/Calpastatin System as a New Strategy to Prevent Cardiovascular Remodeling in Angiotensin II–Induced Hypertension

Emmanuel Letavernier, Joëlle Perez, Agnès Bellocq, Laurent Mesnard, Alexandre de Castro Keller, Jean-Philippe Haymann, Laurent Baud

From the Institut National de la Santé et de la Recherche Médicale (E.L., J.P., A.B., L.M., J.-P.H., L.B.), U702, Paris; Université Pierre et Marie Curie-Paris6 (E.L., J.P., A.B., L.M., J.-P.H., L.B.), UMRS702, Paris; Assistance Publique-Hôpitaux de Paris (E.L., A.B., J.-P.H., L.B.), Tenon Hospital, Department of Physiology, Paris; and Centre National de la Recherche Scientifique (A.d.C.K.), UMR8147, Paris, France.

Correspondence to Laurent Baud, MD, PhD, INSERM U702, Hôpital Tenon, 4 rue de la Chine, 75020 Paris, France. E-mail laurent.baud{at}tnn ap-hop-paris.fr

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.

Key Words: angiotensin • calpain • remodeling • nuclear factor--B

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