食塩/アルドステロン負荷ラットにおけるフィネレノンの心保護効果には心筋Na蓄積抑制が関与する

抄録

Finerenone, a nonsteroidal mineralocorticoid-receptor blocker, has been shown in clinical trials to have considerable cardioprotective benefits. However, its precise mechanism is not clear. Here, we aimed to test the hypothesis that cardioprotective effects of finerenone are linked to a decrease in salt buildup and, as a result, a lower macrophage chemotaxis and/or a change in its phenotype in heart tissues. First, effects of finerenone (10 mg/kg body weight by oral gavage) on myocardial injury and sodium accumulation were examined in uninephrectomized (UNx) Sprague-Dawley rats with chronic aldosterone infusion (0.75 μg/hr) and salt-loading through drinking water (1% NaCl) for 4 weeks. Echocardiography and gene expression analyses revealed an adverse cardiac remodeling as well as diastolic dysfunction with preserved ejection fraction. Notably, finerenone treatment completely prevented the cardiac dysfunction with the improved cardiac remodeling in these rats. Furthermore, sodium content in left ventricular tissues were markedly elevated in salt-loaded aldosterone-infused UNx rats, but significantly reduced in rats with concomitant finerenone treatment. Moreover, gene expression of F4/80 (a macrophage marker) was significantly reduced by finerenone treatment. Apart from that, finerenone dramatically reduced the salt-induced elevation in M1 markers (TNF-alpha and iNOS) in RAW264.7 cells, whereas M2 markers remained unaltered. These data indicate that finerenone has the potential to mitigate cardiac dysfunction in salt-loaded and aldosterone-infused rats by suppressing sodium accumulation in left ventricular tissues. These effects of finerenone may attenuate the subsequent inflammation by macrophages and adverse cardiovascular remodeling.