title: Calpain protects the heart from hemodynamic stress.
abstract: Calpains make up a family of Ca(2+)-dependent intracellular cysteine proteases that include ubiquitously expressed μ- and m-calpains. Both are heterodimers consisting of a distinct large catalytic subunit (calpain 1 for μ-calpain and calpain 2 for m-calpain) and a common regulatory subunit (calpain 4). The physiological roles of calpain remain unclear in the organs, including the heart, but it has been suggested that calpain is activated by Ca(2+) overload in diseased hearts, resulting in cardiac dysfunction. In this study, cardiac-specific calpain 4-deficient mice were generated to elucidate the role of calpain in the heart in response to hemodynamic stress. Cardiac-specific deletion of calpain 4 resulted in decreased protein levels of calpains 1 and 2 and showed no cardiac phenotypes under base-line conditions but caused left ventricle dilatation, contractile dysfunction, and heart failure with interstitial fibrosis 1 week after pressure overload. Pressure-overloaded calpain 4-deficient hearts took up a membrane-impermeant dye, Evans blue, indicating plasma membrane disruption. Membrane repair assays using a two-photon laser-scanning microscope revealed that calpain 4-deficient cardiomyocytes failed to reseal a plasma membrane that had been disrupted by laser irradiation. Thus, the data indicate that calpain protects the heart from hemodynamic stresses, such as pressure overload.
authors.affiliation: Departments of Cardiovascular Medicine, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, USA.
authors.forename: Manabu
authors.initials: M
authors.lastname: Taneike
authors.forename: Isamu
authors.initials: I
authors.lastname: Mizote
authors.forename: Takashi
authors.initials: T
authors.lastname: Morita
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Watanabe
authors.forename: Shungo
authors.initials: S
authors.lastname: Hikoso
authors.forename: Osamu
authors.initials: O
authors.lastname: Yamaguchi
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Takeda
authors.forename: Takafumi
authors.initials: T
authors.lastname: Oka
authors.forename: Takahito
authors.initials: T
authors.lastname: Tamai
authors.forename: Jota
authors.initials: J
authors.lastname: Oyabu
authors.forename: Tomokazu
authors.initials: T
authors.lastname: Murakawa
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Nakayama
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Nishida
authors.forename: Junji
authors.initials: J
authors.lastname: Takeda
authors.forename: Naoki
authors.initials: N
authors.lastname: Mochizuki
authors.forename: Issei
authors.initials: I
authors.lastname: Komuro
authors.forename: Kinya
authors.initials: K
authors.lastname: Otsu
mesh_terms: D000818:Animals; D001794:Blood Pressure; D002118:Calcium / Q000378:metabolism; D002154:Calpain / Q000235:genetics / Q000378:metabolism*; D002462:Cell Membrane / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D006333:Heart Failure / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D009200:Myocardial Contraction; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D013312:Stress, Physiological
chemical_list: D009124:Muscle Proteins; D002154:Calpain; D002118:Calcium