Suppressed soluble Fms–like tyrosine kinase-1 production aggravates atherosclerosis in chronic kidney disease

Abstract

Patients with chronic kidney disease (CKD) die of cardiovascular diseases for unknown reasons. Blood vessel formation in plaques and its relationship with plaque stability could be involved with signaling through the Flt-1 receptor and its ligands, vascular endothelial growth factor, and the closely related placental growth factor (PlGF). Flt-1 also exists as a circulating regulatory splice variant short-inhibitory form (sFlt-1) that serves as a decoy receptor, thereby inactivating PlGF. Heparin releases sFlt-1 by displacing the sFlt-1 heparin-binding site from heparin sulfate proteoglycans. Heparin could provide diagnostic inference or could also induce an antiangiogenic state. In the present study, postheparin sFlt-1 levels were lower in CKD patients than in control subjects. More importantly, sFlt-1 levels were inversely related to atherosclerosis in CKD patients, and this correlation was more robust after heparin injection, as verified by subsequent cardiovascular events. Knockout of apolipoprotein E (ApoE) and/or sFlt-1 showed that the absence of sFlt-1 worsened atherogenesis in ApoE-deficient mice. Thus, the relationship between atherosclerosis and PlGF signaling, as regulated by sFlt-1, underscores the underappreciated role of heparin in sFlt-1 release. These clinical and experimental data suggest that novel avenues into CKD-dependent atherosclerosis and its detection are warranted.

Suppressed Production of Soluble Fms-Like Tyrosine Kinase-1 Contributes to Myocardial Remodeling and Heart Failure

“…20,21 In our previous study, MCP-1 mRNA was upregulated in peritoneal macrophages in sFlt-1 −/− mice. 4 Furthermore, the present study revealed that macrophages were skewed into the CD68 + CD206 − inflammatory phenotype, and that MCP-1 expression was significantly increased in the pressure-overloaded hearts of sFlt-1 −/− compared with the WT mice. On the basis of these findings, it is likely that MCP-1 acts downstream of PLGF/Flt-1 signaling.…”

“…4,8,39 These findings indicate that postheparin sFlt-1 levels can be a surrogate marker for the total amount of sFlt-1 production. 4 We found that postheparin sFlt-1 levels are reduced by approximately half in dialysis patients compared with healthy subjects. 4 On the basis of these findings, we propose that the suppressed production of sFlt-1 exhibits one of the characteristics of CKD.…”

“…4 We found that postheparin sFlt-1 levels are reduced by approximately half in dialysis patients compared with healthy subjects. 4 On the basis of these findings, we propose that the suppressed production of sFlt-1 exhibits one of the characteristics of CKD. These results raise the possibility that the suppressed production of sFlt-1 may play some role in the progression of CKD-associated heart failure.…”

“…Plasma sFlt-1 levels after heparin injection, in other words, postheparin sFlt-1 levels, are positively correlated with estimated glomerular filtration rate in CKD patients, 4 although preheparin plasma levels of sFlt-1 were increased with the progression of renal failure in agreement with the previous reports. 4,8,39 These findings indicate that postheparin sFlt-1 levels can be a surrogate marker for the total amount of sFlt-1 production. 4 We found that postheparin sFlt-1 levels are reduced by approximately half in dialysis patients compared with healthy subjects.…”

“…Generation of sFlt-1 knockout mice was described previously. 4 Briefly, we created constitutive sFlt-1 knockout mice in which intron 13 of the sFlt-1 gene was deleted and exon13 was directly connected to exon 14, thus preventing alternative splicing at intron 13. Full-length Flt-1 was preserved in these mice.…”