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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.

Targeting aldosterone synthesis and/or release represents a potentially useful approach to the prevention of cardiovascular disease. Aldosterone production is stimulated by angiotensin II (Ang II) or extracellular K+ and is mediated mainly by Ca2+ influx into adrenal glomerulosa cells through T-type calcium channels. We therefore examined the effects of efonidipine, a dual T-type/L-type Ca2+ channel blocker, on aldosterone secretion in the H295R human adrenocarcinoma cell line; 100 nmol/L Ang II and 10 mmol/L K+ respectively increased aldosterone secretion from H295R cells 12-fold and 9-fold over baseline. Efonidipine dose-dependently inhibited both Ang II- and K+-induced aldosterone secretion, and nifedipine, an L-type Ca2+ channel blocker, and mibefradil, a relatively selective T-type channel blocker, similarly inhibited Ang II- and K+-induced aldosterone secretion, but were much less potent than efonidipine. Efonidipine also lowered cortisol secretion most potently among these drugs. Notably, efonidipine and mibefradil also significantly suppressed Ang II- and K+-induced mRNA expression of 11-beta-hydroxylase and aldosterone synthase, which catalyze the final two steps in the aldosterone synthesis, whereas nifedipine reduced only K+-induced enzyme expression. These findings suggest that efonidipine acts via T-type Ca2+ channel blockade to significantly reduce aldosterone secretion, and that this effect is mediated, at least in part, by suppression of 11-beta-hydroxylase and aldosterone synthase expression.