Calpain inhibition in a transgenic model of calpastatin overexpression facilitates reversal of myocardial hypertrophy
Aims It was recently demonstrated that the intracellular signalling phosphatase calcineurin is subject to cleavage by the protease calpain, resulting in a truncated calcineurin fragment that is a strong inductor of myocardial hypertrophy. We now address the question of whether inhibition of calpain...
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| Vydané v: | ESC Heart Failure Ročník 12; číslo 3; s. 2256 - 2266 |
|---|---|
| Hlavní autori: | , , , , , , , , , |
| Médium: | Journal Article |
| Jazyk: | English |
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England
John Wiley & Sons, Inc
01.06.2025
John Wiley and Sons Inc Wiley |
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| ISSN: | 2055-5822, 2055-5822 |
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| Abstract | Aims
It was recently demonstrated that the intracellular signalling phosphatase calcineurin is subject to cleavage by the protease calpain, resulting in a truncated calcineurin fragment that is a strong inductor of myocardial hypertrophy. We now address the question of whether inhibition of calpain function in cardiomyocytes, and thereby prevention of calcineurin truncation, attenuates development of myocardial hypertrophy.
Methods and results
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 ± SD in milligrams per gram: CAST OE, 4.8 ± 0.4; CAST OE + AngII, 7.1 ± 0.5; non‐induced, 4.9 ± 0.4; non‐induced + AngII, 7.2 ± 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 ± 0.5; non‐induced 7.0 ± 0.4; P < 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.
Conclusions
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. |
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| AbstractList | Abstract Aims It was recently demonstrated that the intracellular signalling phosphatase calcineurin is subject to cleavage by the protease calpain, resulting in a truncated calcineurin fragment that is a strong inductor of myocardial hypertrophy. We now address the question of whether inhibition of calpain function in cardiomyocytes, and thereby prevention of calcineurin truncation, attenuates development of myocardial hypertrophy. Methods and results 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 ± SD in milligrams per gram: CAST OE, 4.8 ± 0.4; CAST OE + AngII, 7.1 ± 0.5; non‐induced, 4.9 ± 0.4; non‐induced + AngII, 7.2 ± 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 ± 0.5; non‐induced 7.0 ± 0.4; P < 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. Conclusions 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. Aims It was recently demonstrated that the intracellular signalling phosphatase calcineurin is subject to cleavage by the protease calpain, resulting in a truncated calcineurin fragment that is a strong inductor of myocardial hypertrophy. We now address the question of whether inhibition of calpain function in cardiomyocytes, and thereby prevention of calcineurin truncation, attenuates development of myocardial hypertrophy. Methods and results 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 ± SD in milligrams per gram: CAST OE, 4.8 ± 0.4; CAST OE + AngII, 7.1 ± 0.5; non‐induced, 4.9 ± 0.4; non‐induced + AngII, 7.2 ± 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 ± 0.5; non‐induced 7.0 ± 0.4; P < 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. Conclusions 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. It was recently demonstrated that the intracellular signalling phosphatase calcineurin is subject to cleavage by the protease calpain, resulting in a truncated calcineurin fragment that is a strong inductor of myocardial hypertrophy. We now address the question of whether inhibition of calpain function in cardiomyocytes, and thereby prevention of calcineurin truncation, attenuates development of myocardial hypertrophy. 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 ± SD in milligrams per gram: CAST OE, 4.8 ± 0.4; CAST OE + AngII, 7.1 ± 0.5; non-induced, 4.9 ± 0.4; non-induced + AngII, 7.2 ± 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 ± 0.5; non-induced 7.0 ± 0.4; P < 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. 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. It was recently demonstrated that the intracellular signalling phosphatase calcineurin is subject to cleavage by the protease calpain, resulting in a truncated calcineurin fragment that is a strong inductor of myocardial hypertrophy. We now address the question of whether inhibition of calpain function in cardiomyocytes, and thereby prevention of calcineurin truncation, attenuates development of myocardial hypertrophy.AIMSIt was recently demonstrated that the intracellular signalling phosphatase calcineurin is subject to cleavage by the protease calpain, resulting in a truncated calcineurin fragment that is a strong inductor of myocardial hypertrophy. We now address the question of whether inhibition of calpain function in cardiomyocytes, and thereby prevention of calcineurin truncation, attenuates development of myocardial hypertrophy.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 ± SD in milligrams per gram: CAST OE, 4.8 ± 0.4; CAST OE + AngII, 7.1 ± 0.5; non-induced, 4.9 ± 0.4; non-induced + AngII, 7.2 ± 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 ± 0.5; non-induced 7.0 ± 0.4; P < 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.METHODS AND RESULTSWe 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 ± SD in milligrams per gram: CAST OE, 4.8 ± 0.4; CAST OE + AngII, 7.1 ± 0.5; non-induced, 4.9 ± 0.4; non-induced + AngII, 7.2 ± 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 ± 0.5; non-induced 7.0 ± 0.4; P < 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.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.CONCLUSIONSOur 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. Aims It was recently demonstrated that the intracellular signalling phosphatase calcineurin is subject to cleavage by the protease calpain, resulting in a truncated calcineurin fragment that is a strong inductor of myocardial hypertrophy. We now address the question of whether inhibition of calpain function in cardiomyocytes, and thereby prevention of calcineurin truncation, attenuates development of myocardial hypertrophy. Methods and results 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 ± SD in milligrams per gram: CAST OE, 4.8 ± 0.4; CAST OE + AngII, 7.1 ± 0.5; non‐induced, 4.9 ± 0.4; non‐induced + AngII, 7.2 ± 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 ± 0.5; non‐induced 7.0 ± 0.4; P < 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. Conclusions 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. |
| Author | Pagonas, Nikolaos Buschmann, Ivo Ritter, Oliver Sachse, Gregor Tennigkeit, Johanna Hillmeister, Philipp Nordbeck, Peter Czolbe, Martin Schmitt, Joachim Patschan, Daniel |
| AuthorAffiliation | 2 Brandenburg Medical School Neuruppin Germany 6 Comprehensive Heart Failure Center University Hospital Würzburg Würzburg Germany 8 Research Center Magnetic Resonance Bavaria Würzburg Germany 5 Department of Internal Medicine I—Cardiology University Hospital Würzburg Würzburg Germany 1 Department of Internal Medicine I University Hospital Brandenburg Brandenburg an der Havel Germany 7 Department of Experimental Physics V Julius‐Maximilians‐University Würzburg Germany 3 Faculty of Health Sciences Joint Faculty of the Brandenburg University of Technology Cottbus, MHB Theodor Fontane, University of Potsdam Senftenberg Germany 4 Department of Cardiology University Hospital Ruppin‐Brandenburg Neuruppin Germany 9 Institut für Pharmakologie und Toxikologie Universität Düsseldorf Düsseldorf Germany |
| AuthorAffiliation_xml | – name: 7 Department of Experimental Physics V Julius‐Maximilians‐University Würzburg Germany – name: 2 Brandenburg Medical School Neuruppin Germany – name: 6 Comprehensive Heart Failure Center University Hospital Würzburg Würzburg Germany – name: 1 Department of Internal Medicine I University Hospital Brandenburg Brandenburg an der Havel Germany – name: 3 Faculty of Health Sciences Joint Faculty of the Brandenburg University of Technology Cottbus, MHB Theodor Fontane, University of Potsdam Senftenberg Germany – name: 9 Institut für Pharmakologie und Toxikologie Universität Düsseldorf Düsseldorf Germany – name: 4 Department of Cardiology University Hospital Ruppin‐Brandenburg Neuruppin Germany – name: 5 Department of Internal Medicine I—Cardiology University Hospital Würzburg Würzburg Germany – name: 8 Research Center Magnetic Resonance Bavaria Würzburg Germany |
| Author_xml | – sequence: 1 givenname: Gregor orcidid: 0000-0001-5096-4922 surname: Sachse fullname: Sachse, Gregor email: Gregor.Sachse@mhb-fontane.de organization: Joint Faculty of the Brandenburg University of Technology Cottbus, MHB Theodor Fontane, University of Potsdam – sequence: 2 givenname: Johanna surname: Tennigkeit fullname: Tennigkeit, Johanna organization: Joint Faculty of the Brandenburg University of Technology Cottbus, MHB Theodor Fontane, University of Potsdam – sequence: 3 givenname: Nikolaos surname: Pagonas fullname: Pagonas, Nikolaos organization: University Hospital Ruppin‐Brandenburg – sequence: 4 givenname: Philipp surname: Hillmeister fullname: Hillmeister, Philipp organization: Joint Faculty of the Brandenburg University of Technology Cottbus, MHB Theodor Fontane, University of Potsdam – sequence: 5 givenname: Ivo surname: Buschmann fullname: Buschmann, Ivo organization: Joint Faculty of the Brandenburg University of Technology Cottbus, MHB Theodor Fontane, University of Potsdam – sequence: 6 givenname: Martin surname: Czolbe fullname: Czolbe, Martin organization: University Hospital Würzburg – sequence: 7 givenname: Peter surname: Nordbeck fullname: Nordbeck, Peter organization: Julius‐Maximilians‐University – sequence: 8 givenname: Joachim surname: Schmitt fullname: Schmitt, Joachim organization: Universität Düsseldorf – sequence: 9 givenname: Daniel surname: Patschan fullname: Patschan, Daniel organization: Joint Faculty of the Brandenburg University of Technology Cottbus, MHB Theodor Fontane, University of Potsdam – sequence: 10 givenname: Oliver surname: Ritter fullname: Ritter, Oliver organization: Joint Faculty of the Brandenburg University of Technology Cottbus, MHB Theodor Fontane, University of Potsdam |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/40025327$$D View this record in MEDLINE/PubMed |
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| Copyright | 2025 The Author(s). ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology. 2025. This work is published under http://creativecommons.org/licenses/by/4.0/ (the "License"). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License. |
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| Keywords | Heart failure Signal transduction Myocardial hypertrophy |
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It was recently demonstrated that the intracellular signalling phosphatase calcineurin is subject to cleavage by the protease calpain, resulting in a... It was recently demonstrated that the intracellular signalling phosphatase calcineurin is subject to cleavage by the protease calpain, resulting in a truncated... Aims It was recently demonstrated that the intracellular signalling phosphatase calcineurin is subject to cleavage by the protease calpain, resulting in a... Abstract Aims It was recently demonstrated that the intracellular signalling phosphatase calcineurin is subject to cleavage by the protease calpain, resulting... |
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| SubjectTerms | Angiotensin II Animals Antibodies Calcineurin - metabolism Calcium-Binding Proteins - biosynthesis Calcium-Binding Proteins - genetics Calpain - antagonists & inhibitors Calpain - metabolism Cardiomegaly - genetics Cardiomegaly - metabolism Cardiomyocytes Cloning Disease Models, Animal Heart failure Magnetic resonance imaging Mice Mice, Transgenic Myocardial hypertrophy Myocytes, Cardiac - metabolism Myocytes, Cardiac - pathology Original Proteins Signal transduction Statistical analysis Transgenic animals |
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| Title | Calpain inhibition in a transgenic model of calpastatin overexpression facilitates reversal of myocardial hypertrophy |
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