Pharmacological- and gene therapy-based inhibition of protein kinase Cα/β enhances cardiac contractility and attenuates heart failure

Michael Hambleton, Harvey Hahn, Sven T. Pleger, Matthew C. Kuhn, Raisa Klevitsky, Andrew N. Carr, Thomas F. Kimball, Timothy Hewett, Gerald W. Dorn, Walter J. Koch, Jeffery D. Molkentin

Research output: Contribution to journalArticle

108 Citations (Scopus)

Abstract

BACKGROUND - The conventional protein kinase C (PKC) isoform α functions as a proximal regulator of Ca handling in cardiac myocytes. Deletion of PKCα in the mouse results in augmented sarcoplasmic reticulum Ca loading, enhanced Ca transients, and augmented contractility, whereas overexpression of PKCα in the heart blunts contractility. Mechanistically, PKCα directly regulates Ca handling by altering the phosphorylation status of inhibitor-1, which in turn suppresses protein phosphatase-1 activity, thus modulating phospholamban activity and secondarily, the sarcoplasmic reticulum Ca ATPase. METHODS AND RESULTS - In the present study, we show that short-term inhibition of the conventional PKC isoforms with Ro-32-0432 or Ro-31-8220 significantly augmented cardiac contractility in vivo or in an isolated work-performing heart preparation in wild-type mice but not in PKCα-deficient mice. Ro-32-0432 also increased cardiac contractility in 2 different models of heart failure in vivo. Short-term or long-term treatment with Ro-31-8220 in a mouse model of heart failure due to deletion of the muscle lim protein gene significantly augmented cardiac contractility and restored pump function. Moreover, adenovirus-mediated gene therapy with a dominant-negative PKCα cDNA rescued heart failure in a rat model of postinfarction cardiomyopathy. PKCα was also determined to be the dominant conventional PKC isoform expressed in the adult human heart, providing potential relevance of these findings to human pathophysiology. CONCLUSIONS - Pharmacological inhibition of PKCα, or the conventional isoforms in general, may serve as a novel therapeutic strategy for enhancing cardiac contractility in certain stages of heart failure.

Original languageEnglish (US)
Pages (from-to)574-582
Number of pages9
JournalCirculation
Volume114
Issue number6
DOIs
StatePublished - Aug 2006
Externally publishedYes

Fingerprint

Genetic Therapy
Protein Kinase C
Heart Failure
Pharmacology
Protein Isoforms
Sarcoplasmic Reticulum
Myocardial Contraction
Protein Phosphatase 1
Muscle Proteins
Cardiomyopathies
Cardiac Myocytes
Adenoviridae
Adenosine Triphosphatases
Complementary DNA
Phosphorylation
Therapeutics

Keywords

  • Cardiomyopathy
  • Contractility
  • Heart failure
  • Protein kinase C

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Hambleton, M., Hahn, H., Pleger, S. T., Kuhn, M. C., Klevitsky, R., Carr, A. N., ... Molkentin, J. D. (2006). Pharmacological- and gene therapy-based inhibition of protein kinase Cα/β enhances cardiac contractility and attenuates heart failure. Circulation, 114(6), 574-582. https://doi.org/10.1161/CIRCULATIONAHA.105.592550

Pharmacological- and gene therapy-based inhibition of protein kinase Cα/β enhances cardiac contractility and attenuates heart failure. / Hambleton, Michael; Hahn, Harvey; Pleger, Sven T.; Kuhn, Matthew C.; Klevitsky, Raisa; Carr, Andrew N.; Kimball, Thomas F.; Hewett, Timothy; Dorn, Gerald W.; Koch, Walter J.; Molkentin, Jeffery D.

In: Circulation, Vol. 114, No. 6, 08.2006, p. 574-582.

Research output: Contribution to journalArticle

Hambleton, M, Hahn, H, Pleger, ST, Kuhn, MC, Klevitsky, R, Carr, AN, Kimball, TF, Hewett, T, Dorn, GW, Koch, WJ & Molkentin, JD 2006, 'Pharmacological- and gene therapy-based inhibition of protein kinase Cα/β enhances cardiac contractility and attenuates heart failure', Circulation, vol. 114, no. 6, pp. 574-582. https://doi.org/10.1161/CIRCULATIONAHA.105.592550
Hambleton, Michael ; Hahn, Harvey ; Pleger, Sven T. ; Kuhn, Matthew C. ; Klevitsky, Raisa ; Carr, Andrew N. ; Kimball, Thomas F. ; Hewett, Timothy ; Dorn, Gerald W. ; Koch, Walter J. ; Molkentin, Jeffery D. / Pharmacological- and gene therapy-based inhibition of protein kinase Cα/β enhances cardiac contractility and attenuates heart failure. In: Circulation. 2006 ; Vol. 114, No. 6. pp. 574-582.
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abstract = "BACKGROUND - The conventional protein kinase C (PKC) isoform α functions as a proximal regulator of Ca handling in cardiac myocytes. Deletion of PKCα in the mouse results in augmented sarcoplasmic reticulum Ca loading, enhanced Ca transients, and augmented contractility, whereas overexpression of PKCα in the heart blunts contractility. Mechanistically, PKCα directly regulates Ca handling by altering the phosphorylation status of inhibitor-1, which in turn suppresses protein phosphatase-1 activity, thus modulating phospholamban activity and secondarily, the sarcoplasmic reticulum Ca ATPase. METHODS AND RESULTS - In the present study, we show that short-term inhibition of the conventional PKC isoforms with Ro-32-0432 or Ro-31-8220 significantly augmented cardiac contractility in vivo or in an isolated work-performing heart preparation in wild-type mice but not in PKCα-deficient mice. Ro-32-0432 also increased cardiac contractility in 2 different models of heart failure in vivo. Short-term or long-term treatment with Ro-31-8220 in a mouse model of heart failure due to deletion of the muscle lim protein gene significantly augmented cardiac contractility and restored pump function. Moreover, adenovirus-mediated gene therapy with a dominant-negative PKCα cDNA rescued heart failure in a rat model of postinfarction cardiomyopathy. PKCα was also determined to be the dominant conventional PKC isoform expressed in the adult human heart, providing potential relevance of these findings to human pathophysiology. CONCLUSIONS - Pharmacological inhibition of PKCα, or the conventional isoforms in general, may serve as a novel therapeutic strategy for enhancing cardiac contractility in certain stages of heart failure.",
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AU - Klevitsky, Raisa

AU - Carr, Andrew N.

AU - Kimball, Thomas F.

AU - Hewett, Timothy

AU - Dorn, Gerald W.

AU - Koch, Walter J.

AU - Molkentin, Jeffery D.

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N2 - BACKGROUND - The conventional protein kinase C (PKC) isoform α functions as a proximal regulator of Ca handling in cardiac myocytes. Deletion of PKCα in the mouse results in augmented sarcoplasmic reticulum Ca loading, enhanced Ca transients, and augmented contractility, whereas overexpression of PKCα in the heart blunts contractility. Mechanistically, PKCα directly regulates Ca handling by altering the phosphorylation status of inhibitor-1, which in turn suppresses protein phosphatase-1 activity, thus modulating phospholamban activity and secondarily, the sarcoplasmic reticulum Ca ATPase. METHODS AND RESULTS - In the present study, we show that short-term inhibition of the conventional PKC isoforms with Ro-32-0432 or Ro-31-8220 significantly augmented cardiac contractility in vivo or in an isolated work-performing heart preparation in wild-type mice but not in PKCα-deficient mice. Ro-32-0432 also increased cardiac contractility in 2 different models of heart failure in vivo. Short-term or long-term treatment with Ro-31-8220 in a mouse model of heart failure due to deletion of the muscle lim protein gene significantly augmented cardiac contractility and restored pump function. Moreover, adenovirus-mediated gene therapy with a dominant-negative PKCα cDNA rescued heart failure in a rat model of postinfarction cardiomyopathy. PKCα was also determined to be the dominant conventional PKC isoform expressed in the adult human heart, providing potential relevance of these findings to human pathophysiology. CONCLUSIONS - Pharmacological inhibition of PKCα, or the conventional isoforms in general, may serve as a novel therapeutic strategy for enhancing cardiac contractility in certain stages of heart failure.

AB - BACKGROUND - The conventional protein kinase C (PKC) isoform α functions as a proximal regulator of Ca handling in cardiac myocytes. Deletion of PKCα in the mouse results in augmented sarcoplasmic reticulum Ca loading, enhanced Ca transients, and augmented contractility, whereas overexpression of PKCα in the heart blunts contractility. Mechanistically, PKCα directly regulates Ca handling by altering the phosphorylation status of inhibitor-1, which in turn suppresses protein phosphatase-1 activity, thus modulating phospholamban activity and secondarily, the sarcoplasmic reticulum Ca ATPase. METHODS AND RESULTS - In the present study, we show that short-term inhibition of the conventional PKC isoforms with Ro-32-0432 or Ro-31-8220 significantly augmented cardiac contractility in vivo or in an isolated work-performing heart preparation in wild-type mice but not in PKCα-deficient mice. Ro-32-0432 also increased cardiac contractility in 2 different models of heart failure in vivo. Short-term or long-term treatment with Ro-31-8220 in a mouse model of heart failure due to deletion of the muscle lim protein gene significantly augmented cardiac contractility and restored pump function. Moreover, adenovirus-mediated gene therapy with a dominant-negative PKCα cDNA rescued heart failure in a rat model of postinfarction cardiomyopathy. PKCα was also determined to be the dominant conventional PKC isoform expressed in the adult human heart, providing potential relevance of these findings to human pathophysiology. CONCLUSIONS - Pharmacological inhibition of PKCα, or the conventional isoforms in general, may serve as a novel therapeutic strategy for enhancing cardiac contractility in certain stages of heart failure.

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