Bcl10 Mediates Angiotensin II–Induced Cardiac Damage and Electrical Remodeling Academic Article uri icon

abstract

  • Angiotensin (Ang) II is a potent mediator of both hypertension and cardiac damage; however, the mechanisms by which this occur remain unclear. B-cell lymphoma/leukemia 10 (Bcl10) is a member of the CBM signalosome, which links Ang II and nuclear factor-κB signaling. We hypothesized that Bcl10 is pivotal in the pathogenesis of Ang II-induced cardiac damage. Ang II infusion in mice lacking Bcl10 resulted in reduced cardiac fibrosis, less cellular infiltration, and improved arrhythmogenic electric remodeling, despite a similar degree of hypertension or cardiac hypertrophy. Adoptive transfer of bone marrow (BM), whereby Bcl10 knockout or wildtype BM was transferred to their opposite genotype recipients, revealed the dual importance of Bcl10 within both cardiac and immune cells. Loss of Bcl10 in cardiac cells resulted in reduced expression of genes important for the adhesion and recruitment of immune cells. In vitro experiments demonstrated that adhesion of monocytes to Ang II-treated endothelial cells also required Bcl10. Additionally, Bcl10 deficiency in macrophages reduced their intrinsic migratory ability. To address the role of BM-derived fibroblasts in the formation of cardiac fibrosis, we explored whether Bcl10 is also important for the infiltration of BM-derived (myo)fibroblasts into the heart. The transfer of green fluorescent protein positive wildtype BM into Bcl10 knockout recipient mice revealed a reduced number of noncardiac (myo)fibroblasts compared with those wildtype recipients. Our results demonstrate the significant role of Bcl10 in multiple cell types important for the generation of Ang II-induced cardiac damage and electric remodeling and may provide a new avenue for therapeutic intervention.

authors

  • Markó, Lajos
  • Henke, Norbert
  • Park, Joon-Keun
  • Spallek, Bastian
  • Qadri, Fatimunnisa
  • Balogh, András
  • Apel, Ingrid J
  • Oravecz-Wilson, Katherine I
  • Choi, Mira
  • Przybyl, Lukasz
  • Binger, Katrina J
  • Haase, Nadine
  • Wilck, Nicola
  • Heuser, Arnd
  • Fokuhl, Verena
  • Ruland, Jürgen
  • Lucas, Peter C
  • McAllister-Lucas, Linda M
  • Luft, Friedrich C
  • Dechend, Ralf
  • Müller, Dominik N

publication date

  • 2014