Abstract
Background: Uremic cardiomyopathy is responsible for high morbidity and mortality in patients with chronic kidney disease (CKD), which is characterized by cardiac hypertrophy and heart failure. But precise mechanisms are still unknown. In our previous data, soluble Flt-1 (sFlt-1), which is an endogenous inhibitor of PLGF (placental growth factor), is a key molecule of cardiovascular disease in CKD. Soluble Flt-1 production was decreased with the progression of renal diseases, and sFlt-1 deficiency resulted in progression of cardiac hypertrophy and heart failure, which was revealed by using sFlt-1 KO mice (sFlt-1 -/- ). In this study, we examined the novel mechanisms of heart failure and cardiac hypertrophy using sFlt-1 -/- mice which mimic the CKD condition. Methods and Results: We performed transverse aortic constriction (TAC) in sFlt-1 -/- and WT, and evaluated after 7 days. 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 -/- . In addition, MCP-1 expression was increased in the hearts of sFlt-1 -/- compared to WT after TAC. Echocardiographic analysis showed that inhibition of MCP-1 with neutralizing antibody prevented cardiac hypertrophy and systolic dysfunction in sFlt-1 -/- , which implied that MCP-1 was one of the key chemokines for the progression of heart failure in sFlt-1 deficiency. Human cardiac biopsy samples revealed that macrophage mobilization, fibrosis, and MCP-1 expression were increased in uremic cardiomyopathy, which was quite similar to sFlt-1 -/- . Conclusions: The present study demonstrated that PLGF activation in CKD by decrement of sFlt-1 induced macrophage activation and MCP-1 up-regulation which led to cardiac hypertrophy and heart failure. PLGF and MCP-1 are novel mechanisms and therapeutic target of cardiac hypertrophy and heart failure in CKD.
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