Abstract 12145: Imbalance of Placental Growth Factor and Soluble Flt-1 Agrravates Atherosclerosis in Ckd Patients
Chronic kidney disease (CKD) is associated with accelerated atherosclerotic cardiovascular disease, however, its underling molecular mechanism is not fully understood. Placental growth factor (PlGF) plays important roles in the development of atherosclerosis, which is antagonized by a soluble Flt-1(sFlt-1). sFlt-1 circulates as well as is stored on cell surface through binding to heparan sulfate proteogricans. In our study, expression of sFlt-1 mRNA was decreased with progression of CKD in human renal biopsy samples, and decreased in the kidney and lung of 5/6 nephrectomized mice. However, plasma level of sFlt-1 was increased in accordance with severity of CKD in 273 patients with CKD. In contrast, after very small dose of heparin injection (0.4IU/kg), the plasma sFlt-1 level was elevated more in patients with higher eGFR. Consequently, the plasma sFlt-1 level was lower in patients with more reduced renal function after heparin injection. Next, we performed in vitro experiments. Heparin stimulated the release of sFlt-1 from ex vivo organ culture model of mouse thoracic aorta and from cultured human microvascular endothelial cells. It would be likely, therefore, that heparin releases sFlt-1 from cell surface, and that heparin-induced plasma sFlt-1 level is a surrogate marker for both circulating and stored sFlt-1, that is, total amount of sFlt-1 in the body. The of plasma PlGF/sFlt-1 ratio after heparin injection was positively correlated with eGFR, and associated with severity of coronary artery disease. Moreover patients with higher PlGF/sFlt-1 ratio after heparin injection had significantly higher risk of cardiovascular event, but that before heparin did not. Atherosclerotic plaque area and macrophage infiltration into the plaque were significantly increased in 5/6 nephrectomized ApoE-deficient mice associated with reduction of sFlt-1 production in tissues. Replacement therapy with recombinant sFlt-1 significantly reduced atherosclerotic plaque formation. sFlt-1-/-ApoE-/- mice had more atherosclerotic lesion than sFlt-1+/+ApoE-/- mice in spite of their normal renal function.In conclusion imbalance of PlGF and sFlt-1 would be involved in the exaggeration of atherosclerosis in CKD.
- © 2012 by American Heart Association, Inc.