Does genetic deletion or pharmacological inhibition of VAP1 reduce cardiac fibrosis and improve heart function in a mouse model of pressure overload?
VAP1 promotes fibroblast-to-myofibroblast transition, and its targeted inhibition attenuates cardiac fibrosis and preserves heart function in preclinical models of pressure overload.
Abstract Excessive fibrogenesis is associated with adverse cardiac remodeling and heart failure. Myofibroblast, primarily derived resident fibroblast, is the effector cell type in cardiac fibrosis. The mechanism whereby fibroblast–myofibroblast transition is driven remains incompletely understood. In the present study, we investigated the role and targetability of vascular adhesion protein 1 (VAP1) in cardiac fibrosis. Transcriptomic screening identified VAP1 as a direct target for megakaryocytic leukemia 1 (MKL1), a master regulator of tissue fibrosis. VAP1 silencing in primary cardiac fibroblasts down-regulated expression of myofibroblast markers and weakened cell proliferation/migration/contraction when exposed to transforming growth factor-β, whereas VAP1 over-expression exerted the opposite effects. Importantly, VAP1 deletion in quiescent fibroblasts or activated fibroblasts (myofibroblasts), achieved through the Col1a2 -Cre driver and the Postn -Cre driver, respectively, dampened cardiac fibrosis and rescued heart function in mice subjected to the transverse aortic constriction procedure. Data obtained from multi-omics techniques indicated that VAP1 influenced fibroblast–myofibroblast transition by directly interacting with platelet-derived growth factor receptor-beta to enable signal transduction. Finally, small-molecule VAP1 inhibitors attenuated cardiac fibrosis and improved heart function in mice. In conclusion, our data support a role for VAP1 in driving fibroblast activation and cardiac fibrosis. Therefore, targeting VAP1 can be considered as a reasonable approach for the intervention of heart failure.
Huang et al. (Mon,) studied this question.