title: Adult cardiac fibroblast proliferation is modulated by calcium/calmodulin-dependent protein kinase II in normal and hypertrophied hearts.
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.
authors.affiliation: Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, G12 8QQ, UK.
authors.forename: Tamara P
authors.initials: TP
authors.lastname: Martin
authors.forename: Ahmed
authors.initials: A
authors.lastname: Lawan
authors.forename: Emma
authors.initials: E
authors.lastname: Robinson
authors.forename: David J
authors.initials: DJ
authors.lastname: Grieve
authors.forename: Robin
authors.initials: R
authors.lastname: Plevin
authors.forename: Andrew
authors.initials: A
authors.lastname: Paul
authors.forename: Susan
authors.initials: S
authors.lastname: Currie
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism*; D006332:Cardiomegaly / Q000503:physiopathology*; D049109:Cell Proliferation / Q000187:drug effects; D005347:Fibroblasts / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D032383:Myocytes, Cardiac / Q000378:metabolism
chemical_list: D000804:Angiotensin II; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2