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 is rapidly produced in infarct myocardium, especially by endothelial cells during the acute phase of myocardial infarction. Placental growth factor might be over-expressed to compensate the acute ischemic damage, and appears to then act to improve LVEF during the chronic phase.

Background: Placental growth factor (PlGF), a homolog of vascular endothelial growth factor, is reported to stimulate angiogenesis and arteriogenesis in pathological conditions. It was recently demonstrated that PlGF is rapidly produced in myocardial tissue during acute myocardial infarction (MI). However, the effects of exogenous PlGF administration on the healing process after MI are not fully understood. The purpose of the present study was to examine whether PlGF treatment has therapeutic potential in MI. Methods and Results: Recombinant human PlGF (rhPlGF: 10 μg) was administered continuously for 3 days in a mouse model of acute MI. rhPlGF treatment significantly improved survival rate after MI and preserved cardiac function relative to control mice. The numbers of CD31-positive cells and α-smooth muscle actin-positive vessels in the infarct area were significantly increased in the rhPlGF group. Endothelial progenitor cells (Flk-1 + Sca-1 + cells) were mobilized by rhPlGF into the peripheral circulation. Furthermore, rhPlGF promoted the recruitment of GFP-labeled bone marrow cells to the infarct area, but only a few of those migrating cells differentiated into endothelial cells. Conclusions: Exogenous PlGF plays an important role in healing processes by improving cardiac function and stimulating angiogenesis following MI. It can be considered as a new therapeutic molecule. (Circ J 2009; 73: 1674 -1682

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Efonidipine can block both L-and T-type Ca2+ channels. In a previous in vitro study, we clarified that efonid-