Reduction of Circulating Soluble Fms-Like Tyrosine Kinase-1 Plays a Significant Role in Renal Dysfunction–Associated Aggravation of Atherosclerosis

Abstract

Background-Renal dysfunction is commonly accompanied by a worsening of atherosclerosis; however, the underlying molecular mechanism is not fully understood. We examined the role played by soluble fms-like tyrosine kinase-1 (sFlt-1), an endogenous antagonist of the proatherogenic cytokine placental growth factor (PlGF), in the worsening of atherosclerosis in patients with renal dysfunction and in an animal model of renal failure. Methods and Results-In this study, 329 patients who received cardiac catheterization and 76 patients who underwent renal biopsy were enrolled. Both plasma sFlt-1 levels and renal sFlt-1 mRNA expression were positively correlated with estimated glomerular filtration rate (PϽ0.01). The PlGF/sFlt-1 ratio was negatively correlated with estimated glomerular filtration rate (PϽ0.01), whereas plasma PlGF levels were not affected by it. The PlGF/sFlt-1 ratio was significantly higher in patients with multivessel coronary artery disease than in patients with single-vessel or no coronary artery disease. The reduction of circulating sFlt-1 and renal sFlt-1 mRNA levels was confirmed in five-sixths (5/6)-nephrectomized apolipoprotein E-deficient mice that developed experimental renal dysfunction. Atherosclerotic plaque area and macrophage infiltration into the plaque were significantly higher in 5/6 -nephrectomized apolipoprotein E-deficient mice than in control mice, but replacement therapy with recombinant sFlt-1 significantly reduced both plaque formation and macrophage infiltration. Conclusions-The present study demonstrates that a reduction in the circulating levels of sFlt-1 is associated with the worsening of atherosclerosis that accompanies renal dysfunction. (Circulation. 2009;120:2470-2477.)Key Words: atherosclerosis Ⅲ coronary disease Ⅲ growth substances Ⅲ heart failure Ⅲ kidney C hronic kidney disease is a worldwide public health problem not only because it leads to end-stage renal failure 1-3 but also because it is an independent risk factor for atherosclerosis-related cardiovascular events. 4,5 Accumulating evidence indicates that atherosclerosis is often worsened in patients with renal dysfunction, 6 -9 and the risk of cardiovascular disease increases sharply as the estimated glomerular filtration rate (eGFR) declines. 10 Additionally, more than 50% of deaths among end-stage renal failure patients are due to cardiovascular events. 11 Although it is clear that most cardiovascular events associated with renal dysfunction result from atherosclerosis, the underlying molecular mechanism responsible for the worsening of atherosclerosis in chronic kidney disease is not yet fully understood. Consequently, an effective therapeutic strategy is still lacking. Clinical Perspective on p 2477Fms-like tyrosine kinase 1 (Flt-1), which is a receptor tyrosine kinase and a member of the vascular endothelial growth factor (VEGF) receptor family, 12 is a specific receptor for placental growth factor (PlGF) and VEGF-A. Soluble Flt-1 (sFlt-1), which consists of the 6 extracellular immunoglobulin-like domains ...

Placental Growth Factor in Patients with Decreased Renal Function

“…This finding suggests that PlGF might be an indicator of CVD and atherosclerotic complications in patients with decreased renal function. This finding is in line with the finding of Onoue et al, 34 where the PlGF/sFlt-1 ratio was significantly higher in patients with multivessel coronary artery disease than in patients with single-vessel or no coronary disease. In the animal part of this study, a reduction in the circulating levels of sFlt-1 was associated with the worsening of atherosclerosis that accompanied renal dysfunction, whereas serum PlGF concentrations were higher in the 5/6-nephrectomized mice.…”

“…Although the PlGF/sFlt-1 ratio was negatively correlated with the estimated glomerular filtration rate, plasma PlGF levels were not affected by it. 34 In addition, our study showed higher levels of PlGF in CHRI patients not yet dialyzed with CVD compared to those patients without CVD. This finding suggests that PlGF might be an indicator of CVD and atherosclerotic complications in patients with decreased renal function.…”

“…The PlGF-sFlt-1 complex was most closely correlated with the severity of atherosclerosis, in both patients with renal dysfunction and 5/6-nephrectomized mice. 34 In a cohort of 190 type 1 diabetic patients with diabetic nephropathy, elevated PlGF levels predicted higher risk of coronary heart disease after 10 years of follow-up, independent of kidney function and established coronary heart disease risk biomarkers. 35 In this study, the PlGF levels in patients with decreased renal function with DM and those patients without DM were not different.…”

Soluble Fms-like Tyrosine Kinase 1 Is a Novel Predictor of Brain Natriuretic Peptide Elevation

“…9,10) PlGF/sFlt-1 levels have been reported to be positively associated with the presence of CAD and the angiographic severity of CAD. 11) In patients with chest pain and acute coronary syndrome, higher PlGF levels have been observed in those with MI and are associated with an increased risk of short-and long-term adverse outcomes. [12][13][14] There are conflicting results regarding circulating sFlt-1 levels in patients with CAD, with some studies noting higher levels during acute MI compared with control pa-tients, 15) and others showing lower plasma sFlt-1 levels in patients during the acute phase of MI compared with control subjects.…”

Endothelial Gab1 Deletion Accelerates Angiotensin II-Dependent Vascular Inflammation and Atherosclerosis in Apolipoprotein E Knockout Mice

“…31 Briefly, after perfusion with saline, the heart, kidneys, and aorta were harvested and fixed with 4% paraformaldehyde-PBS at 4°C overnight. After careful removal of excess adventitial tissue, the aorta was immersed in 60% 2-propanol for 1 min, stained with Oil Red O at 4°C for 24-36 h, and washed in 60% 2-propanol.…”