Abstract 17078: Soluble Flt-1 Deficiency Plays a Significant Role in the Exacerbation of Cardiac Hypertrophy and Heart Failure
Background: Patients with chronic kidney disease (CKD) are at high risk of cardiovascular disease including heart failure, cardiac hypertrophy, and atherosclerosis which is called cardio-renal syndrome (CRS), however, its underling molecular mechanism is not fully understood. In our previous data, soluble Flt-1 (sFlt-1), which is endogenous inhibitor of PLGF (placental growth factor), can be a key molecule of CRS. Soluble Flt-1 production was decreased with the progression of renal diseases, and sFlt-1 deficiency results in progression of atherosclerosis using double knock-out mice (sFlt-1-/-ApoE-/-). In this study, we examined the role of PLGF/Flt-1 system in heart failure and cardiac hypertrophy using sFlt-1-/- mice which mimics CKD condition.
Methods and Results: Soluble Flt-1 deficient mice and their wild type littermates (WT) were subjected to transverse aortic constriction (TAC), and evaluated after 7 days. Almost half of sFlt-1-/- died within 1 week after TAC, though 85% of WT survived. sFlt-1 deficiency aggravated cardiomegaly and lung-weight to body-weight ratios compared with WT after TAC, which indicates sFlt-1-/- is susceptible to heart failure by pressure-overload. LV wall thickening was significantly increased and ejection fraction was decreased in sFlt-1-/- compared to WT by echocardiography. Histological analysis showed that myocardial fibrosis and macrophage infiltration were significantly increased in sFlt-1 KO compared to WT. Anti-PLGF neutralizing antibody (αPLGF: ThromboGenics, Heverlee, Belgium) prevented pressure-overloaded cardiac hypertrophy and cardiac dysfunction after TAC in sFlt-1-/-. Furthermore, αPLGF prevented not only macrophage accumulation but myocardial fibrosis in sFlt-1-/-, which implies PLGF signal is the main cause of cardiac hypertrophy and cardiac dysfunction in sFlt-1-/-. Moreover, recombinant sFlt-1 protein administration prevented the deterioration of cardiac hypertrophy and LV systolic dysfunction following pressure overload in sFlt-1-/-.
Conclusions: The present study demonstrated that sFlt-1 can be a novel therapeutic target for CRS including cardiac hypertrophy and heart failure.
Author Disclosures: A. Seno: None. Y. Takeda: None. M. Matsui: None. Y. Nakada: None. T. Ueda: None. A. Okuda: None. B. Jonckx: None. H. Nakagawa: None. K. Onoue: None. M. Watanabe: None. H. Kawata: None. R. Kawakami: None. S. Uemura: None. Y. Saito: None.
- © 2014 by American Heart Association, Inc.