Abstract 9240: Activation of PPARγ Converts the Mechanism of Flow-Mediated Dilation in Human Microvessels from H2O2 to NO by a Telomerase Dependent Mechanism

Abstract

Reactive oxygen species (ROS) are important modulators of vascular reactivity. Coronary artery disease (CAD) changes the mechanism of human arteriolar flow-mediated dilation (FMD) from NO to hydrogen peroxide (H2O2), a signaling ROS. Increasing evidence shows that mitochondrial ROS (mtROS) production and the longevity of a cell or organism are inversely related. Telomerase activity (TA), prominent in cellular senescence and tissue aging, shows a reciprocal relationship with mtROS production. Rosiglitazone (Rosi) activates peroxisome proliferator-activated receptor γ (PPARγ) resulting in increased telomerase expression. This could mitigate mtROS production, leading to increased NO bioavailability, improved vascular function, and retardation of atherosclerosis. We hypothesized that PPARγ reduces elevated ROS levels in CAD and converts the mechanism of FMD from H2O2 to NO by increasing telomerase activity. Human adipose arterioles (~200 µm) from discarded pericardial tissue were cannulated for videomicroscopy. Dilation to graded degrees of shear was measured in vessels constricted with endothelin-1. Pharmacological inhibition of TA (BIRBR 1532 10 μM 15-20 h) in vessels from healthy individuals shifted the mechanism of FMD from NO to H2O2 (Panel A+B). In arterioles from patients with CAD, Rosi (10 μM 15-20 h) shifted the mechanism of FMD from H2O2 to NO (Panel C). In vessels from patients with CAD, BIBRB1532 prevented the ability of Rosi to convert the mediator of FMD from NO to H2O2 (D). We conclude that PPARγ signaling increases telomerase activity in the vasculature, which plays a critical and acute role in modulating microvascular function.