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Adult cardiac fibroblast proliferation is modulated by calcium/calmodulin-dependent protein kinase II in normal and hypertrophied hearts

  • Molecular and cellular mechanisms of disease
  • Published:
Pflügers Archiv - European Journal of Physiology Aims and scope Submit manuscript

Abstract

Increased adult cardiac fibroblast proliferation results in an increased collagen deposition responsible for the fibrosis accompanying pathological remodelling of the heart. The mechanisms regulating cardiac fibroblast proliferation remain poorly understood. Using a minimally invasive transverse aortic banding (MTAB) mouse model of cardiac hypertrophy, we have assessed fibrosis and cardiac fibroblast proliferation. We have investigated whether calcium/calmodulin-dependent protein kinase IIδ (CaMKIIδ) regulates proliferation in fibroblasts isolated from normal and hypertrophied hearts. It is known that CaMKIIδ plays a central role in cardiac myocyte contractility, but nothing is known of its role in adult cardiac fibroblast function. The MTAB model used here produces extensive hypertrophy and fibrosis. CaMKIIδ protein expression and activity is upregulated in MTAB hearts and, specifically, in cardiac fibroblasts isolated from hypertrophied hearts. In response to angiotensin II, cardiac fibroblasts isolated from MTAB hearts show increased proliferation rates. Inhibition of CaMKII with autocamtide inhibitory peptide inhibits proliferation in cells isolated from both sham and MTAB hearts, with a significantly greater effect evident in MTAB cells. These results are the first to show selective upregulation of CaMKIIδ in adult cardiac fibroblasts following cardiac hypertrophy and to assign a previously unrecognised role to CaMKII in regulating adult cardiac fibroblast function in normal and diseased hearts.

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Abbreviations

AIP:

Autocamtide inhibitory peptide

BW:

Body weight

CaMKII:

Calcium/calmodulin-dependent protein kinase II

FS:

Fractional shortening

GAPDH:

Glyceraldehyde 3-phosphate dehydrogenase

HW:

Heart weight

LVEDD:

Left ventricular end-diastolic dimension

LVESD:

Left ventricular end-systolic dimension

LVEDP:

Left ventricular end-diastolic pressure

MTAB:

Minimally invasive transverse aortic banding

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Acknowledgments

We would like to thank Margaret MacDonald for her expert technical assistance with mouse surgery and David Blatchford for his expertise in cell imaging. This work was supported by the British Heart Foundation (grant no: FS/06/066/21409).

Conflict of interest

The authors declare they have no conflict of interest.

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Authors and Affiliations

  1. Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, G12 8QQ, UK

    Tamara P. Martin

  2. Department of Pharmacology, School of Medicine, Yale University, 333 Cedar Street, New Haven, CT, 06520, USA

    Ahmed Lawan

  3. Centre for Vision and Vascular Science, Queen’s University Belfast, Grosvenor Road, Belfast, BT12 6BA, UK

    Emma Robinson & David J. Grieve

  4. Strathclyde Institute of Pharmacy & Biomedical Sciences, University of Strathclyde, Hamnett Building, Glasgow, G4 0RE, UK

    Robin Plevin, Andrew Paul & Susan Currie

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  1. Tamara P. Martin
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  2. Ahmed Lawan
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Correspondence to Susan Currie.

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The experiments comply with the current laws of the country in which they were performed.

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Martin, T.P., Lawan, A., Robinson, E. et al. Adult cardiac fibroblast proliferation is modulated by calcium/calmodulin-dependent protein kinase II in normal and hypertrophied hearts. Pflugers Arch - Eur J Physiol 466, 319–330 (2014). https://doi.org/10.1007/s00424-013-1326-9

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  • DOI: https://doi.org/10.1007/s00424-013-1326-9

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