title: Calpain-dependent cleavage of N-cadherin is involved in the progression of post-myocardial infarction remodeling.
abstract: Enzymatic proteolysis by calpains, Ca(2+)-dependent intracellular cysteine proteases, has been implicated in pathological processes such as cellular degeneration or death. Here, we investigated the role of calpain activation in the hearts subjected to myocardial infarction. We produced myocardial infarction in Cast(-/-) mice deficient for calpastatin, the specific endogenous inhibitory protein for calpains, and Cast(+/+) mice. The activity of cardiac calpains in Cast(+/+) mice was not elevated within 1 day but showed a gradual elevation after 7 days following myocardial infarction, which was further pronounced in Cast(-/-) mice. Although the prevalence of cardiomyocyte death was indistinguishable between Cast(-/-) and Cast(+/+) mice, Cast(-/-) mice exhibited profound contractile dysfunction and chamber dilatation and showed a significant reduction in survival rate after myocardial infarction as compared with Cast(+/+) mice. Notably, immunofluorescence revealed that at 28 days after myocardial infarction, calpains were activated in cardiomyocytes exclusively at the border zone and that Cast(-/-) mice showed higher intensity and a broader extent of calpain activation at the border zone than Cast(+/+) mice. In the border zone of Cast(-/-) mice, pronounced activation of calpains was associated with a decrease in N-cadherin expression and up-regulation of molecular markers for cardiac hypertrophy and fibrosis. In cultured rat neonatal cardiomyocytes, calpain activation by treatment with ionomycin induced cleavage of N-cadherin and decreased expression levels of β-catenin and connexin 43, which was attenuated by calpain inhibitor. These results thus demonstrate that activation of calpains disassembles cell-cell adhesion at intercalated discs by degrading N-cadherin and thereby promotes left ventricular remodeling after myocardial infarction.
authors.affiliation: From the Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Kudo-Sakamoto
authors.affiliation: Department of Advanced Clinical Science and Therapeutics, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan, CREST, Japan Science and Technology Agency, Chiyoda-ku, Tokyo 102-0075, Japan akazawah-tky@umin.ac.jp.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Akazawa
authors.affiliation: Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, Chuo-ku, Chiba 260-8670, Japan.
authors.forename: Kaoru
authors.initials: K
authors.lastname: Ito
authors.affiliation: Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, Wako, Saitama 351-0198, Japan.
authors.forename: Jiro
authors.initials: J
authors.lastname: Takano
authors.affiliation: From the Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.
authors.forename: Masamichi
authors.initials: M
authors.lastname: Yano
authors.affiliation: From the Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.
authors.forename: Chizuru
authors.initials: C
authors.lastname: Yabumoto
authors.affiliation: CREST, Japan Science and Technology Agency, Chiyoda-ku, Tokyo 102-0075, Japan Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Atsuhiko T
authors.initials: AT
authors.lastname: Naito
authors.affiliation: From the Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan, CREST, Japan Science and Technology Agency, Chiyoda-ku, Tokyo 102-0075, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Oka
authors.affiliation: Department of Cardiovascular Regenerative Medicine, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan, and.
authors.forename: Jong-Kook
authors.initials: JK
authors.lastname: Lee
authors.affiliation: From the Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Sakata
authors.affiliation: Department of Advanced Clinical Science and Therapeutics, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Suzuki
authors.affiliation: Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, Wako, Saitama 351-0198, Japan.
authors.forename: Takaomi C
authors.initials: TC
authors.lastname: Saido
authors.affiliation: CREST, Japan Science and Technology Agency, Chiyoda-ku, Tokyo 102-0075, Japan Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan, komuro-tky@umin.ac.jp.
authors.forename: Issei
authors.initials: I
authors.lastname: Komuro
mesh_terms: D000818:Animals; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D002154:Calpain / Q000235:genetics / Q000378:metabolism*; D018031:Connexin 43 / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D009203:Myocardial Infarction / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D020257:Ventricular Remodeling; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: D015820:Cadherins; D002135:Calcium-Binding Proteins; C489083:Cdh2 protein, mouse; D018031:Connexin 43; C580592:Gja1 protein, rat; D009124:Muscle Proteins; C570099:N-cadherin, rat; D009419:Nerve Tissue Proteins; D051176:beta Catenin; C033668:calpastatin; D002154:Calpain
keywords: Apoptosis; Calcium; Cell Adhesion; Heart Failure; Protease