Essential role of calcineurin/NFAT and ROS in mediating mechanical stretch‐induced leptin synthesis and vascular smooth muscle remodeling

Abstract

Obesity is associated with hypertension and increased leptin production that contribute to cardiovascular pathology. We used rat portal vein (RPV) organ culture to investigate the effect of mechanical stretch (mimicking hypertension) on secretion of leptin and the effect of exogenous leptin (3.1 nM) on vascular smooth muscle VSMC. Stretching the RPV for 1, 2, 3 6 or 12h significantly up‐regulated leptin gene expressions and leptin synthesis and secretion. MS significantly increased ROS production (10 fold), calcineurin (CN) activity (3 fold) and NFAT nuclear translocation, effects that was significantly attenuated by the coadministration of an anti‐leptin receptor antibody (anti‐OBR; 166 ng/ml), the ROCK inhibitor Y‐27632 (10 μM) as well the RhoA inhibitor C3, (30 μg/ml). Disruption of actin microfilaments with 50nM latrunculin B significantly attenuated MS‐induced ROS production, CN activity and NFAT nuclear translocation. The role of ROS in MS‐induced leptin secretion and expression was further established when pretreatment of NADPH oxidase inhibitor apocynin (1 mM) potently attenuated leptin expression, synthesis and secretion induced by MS. Our results indicate that the activation of CN and ROS production plays a pivotal role in MS signaling, leading to leptin synthesis and VSMC hypertrophy.