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 (P<0.01). The PlGF/sFlt-1 ratio was negatively correlated with estimated glomerular filtration rate (P<0.01), 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.

• Authors: Kenji Onoue, Shiro Uemura, Yukiji Takeda, Satoshi Somekawa, Hajime Iwama, Keiichi Imagawa, Taku Nishida, Yoshinobu Morikawa, Yasuhiro Takemoto, Osamu Asai, Tsunenari Soeda, Satoshi Okayama, Kenichi Ishigami, Kimihiko Nakatani, Hiroyuki Kawata, Manabu Horii, Tamio Nakajima, Yasuhiro Akai, Masayuki Iwano, Yoshihiko Saito
• Journal: Circulation (Circulation) Vol. 120 Issue 24 Pg. 2470-7 (Dec 15 2009) ISSN: 1524-4539 [Electronic] United States
• PMID: 19948974 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Apolipoproteins E
• GH2 protein, human
• Placental Hormones
• Growth Hormone
• FLT1 protein, human
• Vascular Endothelial Growth Factor Receptor-1

Topics

• Adult
• Aged
• Animals
• Apolipoproteins E (deficiency)
• Atherosclerosis (enzymology, etiology, physiopathology)
• Disease Models, Animal
• Female
• Growth Hormone (antagonists & inhibitors, blood, physiology)
• Humans
• Kidney Failure, Chronic (enzymology, genetics, physiopathology)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Middle Aged
• Nephrectomy
• Placental Hormones (antagonists & inhibitors, blood, physiology)
• Random Allocation
• Vascular Endothelial Growth Factor Receptor-1 (antagonists & inhibitors, blood, physiology)