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Calpain protects the heart from hemodynamic stress

Research output: Contribution to journalArticlepeer-review

Manabu Taneike, Isamu Mizote, Takashi Morita, Tetsuya Watanabe, Shungo Hikoso, Osamu Yamaguchi, Toshihiro Takeda, Takafumi Oka, Takahito Tamai, Jota Oyabu, Tomokazu Murakawa, Hiroyuki Nakayama, Kazuhiko Nishida, Junji Takeda, Naoki Mochizuki, Issei Komuro, Kinya Otsu

Original languageEnglish
Pages (from-to)32170-7
Number of pages8
JournalNucleic Acids research and the Journal of Biological Chemistry
Volume286
Issue number37
DOIs
Published16 Sep 2011

King's Authors

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.

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