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We now address the question of whether inhibition of calpain function in cardiomyocytes, and thereby prevention of calcineurin truncation, attenuates development of myocardial hypertrophy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and results<\/jats:title>\n                    <jats:p>We generated a transgenic mouse model with conditional cardiac calpastatin overexpression (CAST OE) and compared their cardiac hypertrophic response to angiotensin-II (AngII) with that of non-induced control animals. Angiotensin-II osmotic mini-pumps were removed 3 weeks after implantation and cardiac hypertrophy was re-evaluated 3 weeks after pump removal. Induction of calpastatin overexpression resulted in 88% inhibition of calpain activity and suppressed calcineurin truncation. In CAST OE mice, basal phenotype and AngII-induced myocardial hypertrophy were comparable with non-induced controls (mean heart to body weight ratios \u00b1 SD in milligrams per gram: CAST OE, 4.8 \u00b1 0.4; CAST OE + AngII, 7.1 \u00b1 0.5; non-induced, 4.9 \u00b1 0.4; non-induced + AngII, 7.2 \u00b1 0.4). However, CAST OE mice demonstrated a complete reversal of hypertrophy when angiotensin-II was removed, whereas hypertrophy persisted in non-induced controls (CAST OE 5.0 \u00b1 0.5; non-induced 7.0 \u00b1 0.4; P &amp;lt; 0.0001). Persistent hypertrophy in controls was accompanied by nuclear accumulation of truncated calcineurin and elevated activity of the Nuclear Factor of Activated T-cells pathway. Moreover, we found that truncated calcineurin was insufficiently ubiquitinylated compared with its full-length form and thus escaped degradation over several weeks in our in vivo experiments.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our data demonstrate that calpain-mediated cleavage results in nuclear accumulation of a truncated, constitutively active and degradation-resistant calcineurin isoform that sustains a long-term myocardial hypertrophic response to angiotensin-II beyond withdrawal of the stimulus. Cardiomyocyte specific calpain inhibition by transgenic calpastatin overexpression prevented the post-stimulus myocardial hypertrophic response.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ehf2.15250","type":"journal-article","created":{"date-parts":[[2025,3,11]],"date-time":"2025-03-11T11:16:38Z","timestamp":1741691798000},"page":"2256-2266","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Calpain Inhibition in a Transgenic Model of Calpastatin Overexpression Facilitates Reversal of Myocardial Hypertrophy"],"prefix":"10.1093","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5096-4922","authenticated-orcid":false,"given":"Gregor","family":"Sachse","sequence":"first","affiliation":[{"name":"Department of Internal Medicine I, University Hospital Brandenburg , Brandenburg an der Havel ,","place":["Germany"]},{"name":"Brandenburg Medical School , Neuruppin 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,","place":["Germany"]},{"name":"Brandenburg Medical School , Neuruppin ,","place":["Germany"]},{"name":"Faculty of Health Sciences, Joint Faculty of the Brandenburg University of Technology Cottbus, MHB Theodor Fontane, University of Potsdam , Senftenberg ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Czolbe","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine I\u2014Cardiology, University Hospital W\u00fcrzburg , W\u00fcrzburg ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Nordbeck","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine I\u2014Cardiology, University Hospital W\u00fcrzburg , W\u00fcrzburg ,","place":["Germany"]},{"name":"Comprehensive Heart Failure Center, University Hospital W\u00fcrzburg , W\u00fcrzburg ,","place":["Germany"]},{"name":"Department of Experimental Physics V, Julius-Maximilians-University , W\u00fcrzburg ,","place":["Germany"]},{"name":"Research Center Magnetic Resonance Bavaria , W\u00fcrzburg ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joachim","family":"Schmitt","sequence":"additional","affiliation":[{"name":"Institut f\u00fcr Pharmakologie und Toxikologie, Universit\u00e4t D\u00fcsseldorf , D\u00fcsseldorf ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Patschan","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine I, University Hospital Brandenburg , Brandenburg an der Havel ,","place":["Germany"]},{"name":"Brandenburg Medical School , Neuruppin ,","place":["Germany"]},{"name":"Faculty of Health Sciences, Joint Faculty of the Brandenburg University of Technology Cottbus, MHB Theodor Fontane, University of Potsdam , Senftenberg 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