Reversibility of adverse, calcineurin-dependent cardiac remodeling

Jeff M. Berry, Vien Le, David Rotter, Pavan K. Battiprolu, Bennett Grinsfelder, Paul Tannous, Jana S. Burchfield, Michael Czubryt, Johannes Backs, Eric N. Olson, Beverly A. Rothermel, Joseph A. Hill*

*Corresponding author for this work

Research output: Contribution to journalArticle

43 Citations (Scopus)

Abstract

Rationale: Studies to dissect the role of calcineurin in pathological cardiac remodeling have relied heavily on murine models, in which genetic gain- and loss-of-function manipulations are initiated at or before birth. However, the great majority of clinical cardiac pathology occurs in adults. Yet nothing is known about the effects of calcineurin when its activation commences in adulthood. Furthermore, despite the fact that ventricular hypertrophy is a well-established risk factor for heart failure, the relative pace and progression of these 2 major phenotypic features of heart disease are unknown. Finally, even though therapeutic interventions in adults are designed to slow, arrest, or reverse disease pathogenesis, little is known about the capacity for spontaneous reversibility of calcineurin-dependent pathological remodeling. Objective: We set out to address these 3 questions by studying mice engineered to harbor in cardiomyocytes a constitutively active calcineurin transgene driven by a tetracycline-responsive promoter element. Methods and Results: Expression of the mutant calcineurin transgene was initiated for variable lengths of time to determine the natural history of disease pathogenesis, and to determine when, if ever, these events are reversible. Activation of the calcineurin transgene in adult mice triggered rapid and robust cardiac growth with features characteristic of pathological hypertrophy. Concentric hypertrophy preceded the development of systolic dysfunction, fetal gene activation, fibrosis, and clinical heart failure. Furthermore, cardiac hypertrophy reversed spontaneously when calcineurin activity was turned off, and expression of fetal genes reverted to baseline. Fibrosis, a prominent feature of pathological cardiac remodeling, manifested partial reversibility. Conclusions: Together, these data establish and define the deleterious effects of calcineurin signaling in the adult heart and reveal that calcineurin-dependent hypertrophy with concentric geometry precedes systolic dysfunction and heart failure. Furthermore, these findings demonstrate that during much of the disease process, calcineurin-dependent remodeling remains reversible.

Original languageEnglish (US)
Pages (from-to)407-417
Number of pages11
JournalCirculation research
Volume109
Issue number4
DOIs
StatePublished - Aug 5 2011

Fingerprint

Calcineurin
Hypertrophy
Transgenes
Fibrosis
Heart Failure
Systolic Heart Failure
Clinical Pathology
Cardiomegaly
Cerebral Palsy
Tetracycline
Cardiac Myocytes
Transcriptional Activation
Heart Diseases
Parturition
Gene Expression

Keywords

  • heart failure
  • hypertrophy
  • remodeling

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Berry, J. M., Le, V., Rotter, D., Battiprolu, P. K., Grinsfelder, B., Tannous, P., ... Hill, J. A. (2011). Reversibility of adverse, calcineurin-dependent cardiac remodeling. Circulation research, 109(4), 407-417. https://doi.org/10.1161/CIRCRESAHA.110.228452
Berry, Jeff M. ; Le, Vien ; Rotter, David ; Battiprolu, Pavan K. ; Grinsfelder, Bennett ; Tannous, Paul ; Burchfield, Jana S. ; Czubryt, Michael ; Backs, Johannes ; Olson, Eric N. ; Rothermel, Beverly A. ; Hill, Joseph A. / Reversibility of adverse, calcineurin-dependent cardiac remodeling. In: Circulation research. 2011 ; Vol. 109, No. 4. pp. 407-417.
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Berry, JM, Le, V, Rotter, D, Battiprolu, PK, Grinsfelder, B, Tannous, P, Burchfield, JS, Czubryt, M, Backs, J, Olson, EN, Rothermel, BA & Hill, JA 2011, 'Reversibility of adverse, calcineurin-dependent cardiac remodeling', Circulation research, vol. 109, no. 4, pp. 407-417. https://doi.org/10.1161/CIRCRESAHA.110.228452

Reversibility of adverse, calcineurin-dependent cardiac remodeling. / Berry, Jeff M.; Le, Vien; Rotter, David; Battiprolu, Pavan K.; Grinsfelder, Bennett; Tannous, Paul; Burchfield, Jana S.; Czubryt, Michael; Backs, Johannes; Olson, Eric N.; Rothermel, Beverly A.; Hill, Joseph A.

In: Circulation research, Vol. 109, No. 4, 05.08.2011, p. 407-417.

Research output: Contribution to journalArticle

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T1 - Reversibility of adverse, calcineurin-dependent cardiac remodeling

AU - Berry, Jeff M.

AU - Le, Vien

AU - Rotter, David

AU - Battiprolu, Pavan K.

AU - Grinsfelder, Bennett

AU - Tannous, Paul

AU - Burchfield, Jana S.

AU - Czubryt, Michael

AU - Backs, Johannes

AU - Olson, Eric N.

AU - Rothermel, Beverly A.

AU - Hill, Joseph A.

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N2 - Rationale: Studies to dissect the role of calcineurin in pathological cardiac remodeling have relied heavily on murine models, in which genetic gain- and loss-of-function manipulations are initiated at or before birth. However, the great majority of clinical cardiac pathology occurs in adults. Yet nothing is known about the effects of calcineurin when its activation commences in adulthood. Furthermore, despite the fact that ventricular hypertrophy is a well-established risk factor for heart failure, the relative pace and progression of these 2 major phenotypic features of heart disease are unknown. Finally, even though therapeutic interventions in adults are designed to slow, arrest, or reverse disease pathogenesis, little is known about the capacity for spontaneous reversibility of calcineurin-dependent pathological remodeling. Objective: We set out to address these 3 questions by studying mice engineered to harbor in cardiomyocytes a constitutively active calcineurin transgene driven by a tetracycline-responsive promoter element. Methods and Results: Expression of the mutant calcineurin transgene was initiated for variable lengths of time to determine the natural history of disease pathogenesis, and to determine when, if ever, these events are reversible. Activation of the calcineurin transgene in adult mice triggered rapid and robust cardiac growth with features characteristic of pathological hypertrophy. Concentric hypertrophy preceded the development of systolic dysfunction, fetal gene activation, fibrosis, and clinical heart failure. Furthermore, cardiac hypertrophy reversed spontaneously when calcineurin activity was turned off, and expression of fetal genes reverted to baseline. Fibrosis, a prominent feature of pathological cardiac remodeling, manifested partial reversibility. Conclusions: Together, these data establish and define the deleterious effects of calcineurin signaling in the adult heart and reveal that calcineurin-dependent hypertrophy with concentric geometry precedes systolic dysfunction and heart failure. Furthermore, these findings demonstrate that during much of the disease process, calcineurin-dependent remodeling remains reversible.

AB - Rationale: Studies to dissect the role of calcineurin in pathological cardiac remodeling have relied heavily on murine models, in which genetic gain- and loss-of-function manipulations are initiated at or before birth. However, the great majority of clinical cardiac pathology occurs in adults. Yet nothing is known about the effects of calcineurin when its activation commences in adulthood. Furthermore, despite the fact that ventricular hypertrophy is a well-established risk factor for heart failure, the relative pace and progression of these 2 major phenotypic features of heart disease are unknown. Finally, even though therapeutic interventions in adults are designed to slow, arrest, or reverse disease pathogenesis, little is known about the capacity for spontaneous reversibility of calcineurin-dependent pathological remodeling. Objective: We set out to address these 3 questions by studying mice engineered to harbor in cardiomyocytes a constitutively active calcineurin transgene driven by a tetracycline-responsive promoter element. Methods and Results: Expression of the mutant calcineurin transgene was initiated for variable lengths of time to determine the natural history of disease pathogenesis, and to determine when, if ever, these events are reversible. Activation of the calcineurin transgene in adult mice triggered rapid and robust cardiac growth with features characteristic of pathological hypertrophy. Concentric hypertrophy preceded the development of systolic dysfunction, fetal gene activation, fibrosis, and clinical heart failure. Furthermore, cardiac hypertrophy reversed spontaneously when calcineurin activity was turned off, and expression of fetal genes reverted to baseline. Fibrosis, a prominent feature of pathological cardiac remodeling, manifested partial reversibility. Conclusions: Together, these data establish and define the deleterious effects of calcineurin signaling in the adult heart and reveal that calcineurin-dependent hypertrophy with concentric geometry precedes systolic dysfunction and heart failure. Furthermore, these findings demonstrate that during much of the disease process, calcineurin-dependent remodeling remains reversible.

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