Abstract 3551: Cyclophilin a Promotes Angiotensin II-Induced Inflammation and Cardiovascular Hypertrophy in Mice
Background - Cyclophilin A (CyPA) is a chaperone protein secreted from vascular smooth muscle cells (VSMC) in response to reactive oxygen species (ROS). We have recently demonstrated that extracellular CyPA stimulates at least 3 signaling pathways (ERK1/2, Akt and JAK) and mediates numerous cellular effects of ROS. Angiotensin II (Ang II) induces ROS through NADPH oxidases and activates matrix metalloproteinase (MMP) in VSMC. ROS and MMPs have been demonstrated to mediate cardiac hypertrophy and remodeling. We hypothesized that VSMC-derived CyPA contributes to AngII-induced cardiovascular hypertrophy in vivo due to its proinflammatory properties.
Methods and Results - ApoE−/− and ApoE−/−CyPA−/−mice were treated with AngII (1000 ng/min/kg for 4 weeks) to induce cardiac hypertrophy. Long-term infusion of AngII significantly increased heart/body weight ratio in ApoE−/− mice, which was significantly less in ApoE−/−CyPA−/− mice (6.6±1.0 vs. 4.8±0.7, P<0.01). Echocar-diography confirmed a significantly greater increase in LV mass in ApoE−/− mice compared to ApoE−/−CyPA−/− mice (112% vs. 47%). Perivascular accumulation of inflammatory cells and cardiac myofibroblasts in ApoE−/− mice was significantly greater than in ApoE−/−CyPA−/− mice. Consequently, coronary artery ROS production (DHE fluorescence) and MMP activation (in situ zymography) were markedly increased by AngII in ApoE−/− mice compared to ApoE−/−CyPA−/−mice. To determine the source of CyPA, bone marrow cells (BMCs) transplantation was performed. The heart/body weight ratio was still higher in ApoE−/− mice compared with ApoE−/−CyPA−/− mice after reconstitution with GFP+ CyPA+/+ BMCs (6.7±0.6 vs. 5.6±0.9, P<0.01). Recruitment of GFP+ BMCs to the heart in chimeric ApoE−/− mice was significantly greater than the chimeric ApoE−/−CyPA−/− mice (count/area; 218±63 vs. 109±43, P<0.01). To prove a vascular source of CyPA was essential, VSMC-specific CyPA overexpressing mice were generated. In these mice there was a significant increase in cardiac MMP activity after AngII infusion (VSMC-Tg > WT > CyPA−/−).
Conclusion - CyPA is a novel mediator of AngII-induced cardiac hypertrophy by stimulating vascular ROS production, MMP activation, and inflammatory cell recruitment.
This research has received full or partial funding support from the American Heart Association, AHA Founders Affiliate (Connecticut, Maine, Massachusetts, New Hampshire, New Jersey, New York, Rhode Island, Vermont).