Cyclophilin a promotes cardiac hypertrophy in apolipoprotein e-deficient mice

Objective- Cyclophilin A (CyPA, encoded by Ppia) is a proinflammatory protein secreted in response to oxidative stress in mice and humans. We recently demonstrated that CyPA increased angiotensin II (Ang II)-induced reactive oxygen species (ROS) production in the aortas of apolipoprotein E (apoE ^-/-) mice. In this study, we sought to evaluate the role of CyPA in Ang II-induced cardiac hypertrophy. Methods and Results- Cardiac hypertrophy was not significantly different between Ppia^+/+ and Ppia^-/- mice infused with Ang II (1000 ng/min per kg for 4 weeks). Therefore, we investigated the effect of CyPA under conditions of high ROS and inflammation using the apoE^-/- mice. In contrast to apoE^-/- mice, apoE^-/-Ppia mice exhibited significantly less Ang II-induced cardiac hypertrophy. Bone marrow cell transplantation showed that CyPA in cells intrinsic to the heart plays an important role in the cardiac hypertrophic response. Ang II-induced ROS production, cardiac fibroblast proliferation, and cardiac fibroblast migration were markedly decreased in apoE^-/-Ppia cardiac fibroblasts. Furthermore, CyPA directly induced the hypertrophy of cultured neonatal cardiac myocytes. Conclusion- CyPA is required for Ang II-mediated cardiac hypertrophy by directly potentiating ROS production, stimulating the proliferation and migration of cardiac fibroblasts, and promoting cardiac myocyte hypertrophy.