Abstract 3090: Cyclophilin A Augments ROS Production and Angiotensin II-induced Cardiac Hypertrophy in Mice
Background: Cyclophilin A (CyPA) is an inflammatory protein highly expressed and secreted from vascular smooth muscle cells (VSMC) in mice and humans. We have recently demonstrated that intracellular and extracellular CyPA synergistically augments reactive oxygen species (ROS) production in VSMC. CyPA secretion and Angiotensin II (AngII)-induced ROS production are both augmented in ApoE−/− mice. We hypothesized that AngII and CyPA would synergize in the cardiac hypertrophic response in vivo.
Methods and Results: ApoE−/− and ApoE−/−CyPA−/− mice were treated with AngII (1000 ng/min/kg for 4 weeks) to induce cardiac hypertrophy. In contrast to ApoE−/− mice (n=15), ApoE−/−CyPA−/− mice (n=11) revealed significant reduction of AngII-induced cardiac hypertrophy (% increase of heart/body weight ratio; +51.4% vs. +14.0%, P<0.01). ROS production (DHE fluorescence), MMP activation (in situ zymography), and cardiac fibroblast migration/proliferation were markedly increased by AngII in ApoE−/− mice compared to ApoE−/−CyPA−/− mice. AngII-induced ROS production was significantly reduced in ApoE−/−CyPA−/− mice compared to ApoE−/− mice (1.8±0.2 vs. 5.6±0.4, P<0.01). To determine the source of CyPA, bone marrow cells (BMCs) transplantation was performed. Recruitment of GFP+ BMCs to the heart was significantly reduced in ApoE−/−CyPA−/−mice compared with ApoE−/− mice (count/area; 109±43 vs. 218±63, P<0.01). The heart/body weight ratio remained higher in ApoE−/− mice compared with ApoE−/−CyPA−/− mice after reconstitution with CyPA+/+ BMCs or CyPA−/− BMCs, indicating that CyPA from BMCs does not play a significant role in the cardiac hypertrophic response. To investigate whether extracel-lular/secreted CyPA was essential, we stimulated rat neonatal cardiac myocytes and fibroblasts with recombinant CyPA (CyPA, 100 nM). Extracellular CyPA significantly increased rat neonatal cardiac myocyte hypertrophy (by 3[H] leucine incorporation) and augmented AngII-induced inositol phosphate (IPs) accumulation in rat neonatal cardiac fibroblasts.
Conclusion: CyPA is a novel pathogenic mediator of cardiac hypertrophy by augmenting ROS production, inflammatory cell migration, and direct effects on both cardiac myocytes and fibroblasts.
This research has received full or partial funding support from the American Heart Association, Founders Affiliate (Connecticut, Maine, Massachusetts, New Hampshire, New Jersey, New York, Rhode Island, Vermont).