Crucial Roles of Rho-kinase, Cyclophilin A and its Receptor, Basigin, for Cardiac Hypertrophy, Fibrosis and Failure-Novel Therapeutic Targets

Abstract

The RhoA/Rho-kinase pathway plays an important role in various fundamental cellular functions, including contraction, motility, proliferation and apoptosis, whereas its excessive activity is involved in the pathogenesis of cardiovascular diseases by accelerating migration, proliferation, and inflammation. We have recently demonstrated that cyclophilin A (CyPA) is secreted from VSMC, inflammatory cells, activated platelets and cardiac fibroblasts in response to several stimuli including angiotensin II and mechanical stretch, and promotes cardiac hypertrophy, fibrosis and failure. One of the recent topics is that the secretion of CyPA, an important novel mediator of oxidative stress, is regulated by the RhoA/Rho-kinase system. Moreover, we have shown that basigin (Bsg), a transmembrane glycoprotein that activates MMPs, is one of the extracellular receptor for CyPA and promotes cell proliferation and inflammation. Here, we developed tissue-specific geneticallymodified mice (e.g. DN-ROCK, ROCK1-/-, ROCK2-/-, CyPA+/-, Bsg+/-) and explored their roles in the development of cardiac hypertrophy and failure in mouse models. In vivo and in vitro studies demonstrated that the Rho-kinase-CyPA-Bsg system plays a crucial role in cardiac hypertrophy, fibrosis, inflammation and dysfunction, suggesting that the system is a novel therapeutic target of heart failure (HF) in humans. In a clinical study, we have demonstrated that plasma CyPA levels have prognostic impacts in HF patients, which are further enhanced when combined with BNP. The RhoA/Rho-kinase pathway plays an important role in various fundamental cellular functions, including contraction, motility, proliferation and apoptosis, whereas its excessive activity is involved in the pathogenesis of cardiovascular diseases by accelerating migration, proliferation, and inflammation. We have recently demonstrated that cyclophilin A (CyPA) is secreted from VSMC, inflammatory cells, activated platelets and cardiac fibroblasts in response to several stimuli including angiotensin II and mechanical stretch, and promotes cardiac hypertrophy, fibrosis and failure. One of the recent topics is that the secretion of CyPA, an important novel mediator of oxidative stress, is regulated by the RhoA/Rho-kinase system. Moreover, we have shown that basigin (Bsg), a transmembrane glycoprotein that activates MMPs, is one of the extracellular receptor for CyPA and promotes cell proliferation and inflammation. Here, we developed tissue-specific geneticallymodified mice (e.g. DN-ROCK, ROCK1-/-, ROCK2-/-, CyPA+/-, Bsg+/-) and explored their roles in the development of cardiac hypertrophy and failure in mouse models. In vivo and in vitro studies demonstrated that the Rho-kinase-CyPA-Bsg system plays a crucial role in cardiac hypertrophy, fibrosis, inflammation and dysfunction, suggesting that the system is a novel therapeutic target of heart failure (HF) in humans. In a clinical study, we have demonstrated that plasma CyPA levels have prognostic impacts in HF patients, which are further enhanced when combined with BNP.