Abstract 5043: Telmisartan Enhances Mitochondrial Biogenesis and Protects From Endothelial Cell Damage Through Peroxisome Proliferator-Activated Receptor-γIndependent Pathways
Background Mitochondrial dysfunction in endothelial cells (EC) might be involved in atherogenesis. Telmisartan (TELMI), which has peroxisome proliferator-activated receptor (PPAR)-γ activating properties, has been shown to reduce cardiovascular events in high risk patients. We investigated whether TELMI could modulate mitochondrial function in human coronary artery endothelial cells (HCAEC).
Methods and Results Pretreatment of HCAEC with 10μM TELMI preserved the mitochondrial function from H2O2 exposure (1.0mM, 60min) evaluated by mitochondrial nicotinamide adenine dinucleotide (NADH) levels (NADH: 1.3±0.2 fold greater than vehicle, n=6, p<0.01), and also reduced apoptotic annexin V positive EC induced by H2O2 (100μM, 30min) (% apoptosis EC: vehicle 38.3±3.1%, TELMI 26.0±2.3, n=6, p<0.01). TELMI increased EC mitochondrial number as assessed by fluorescence intensity of MitoTracker Green (vehicle 17.5±0.7, TELMI 21.3±2.1, n=6, p<0.01) and enhanced EC mitochondrial function as assessed by colorimetric NADH assay, in a time and concentration dependent manner (0–48 hours, 0.1–10μM, up to 1.9±0.1 fold, n=7, p<0.01), but other sartans did not have the similar effects. In senescent HCAEC at the 16th passage, TELMI inhibited the appearance of giant EC (vehicle 44.3±5.2/field; TELMI 0.8±1.0, n=6, p<0.01). TELMI treatment significantly enhanced EC tube formation (tube length: 4.1±0.4 fold greater than vehicle, n=5, p<0.01), and we observed significant increases in mRNA expression levels of eNOS, VEGFA, mitochondrial transcription factor A, and Sirt1 in HCAEC after 48 hours TELMI treatment (1.3±0.2, 2.0±0.5, 1.2±0.04, 1.3±0.2 fold, respectively, all p<0.05). To determine the possible involvement of PPARγ pathway, we knocked down PPARγ with siRNA and inhibited PPARγ-mediated signaling by selective PPARγ blockers; GW9662 and T0070907. These two strategies did not affect the increased mitochondrial NADH levels induced by TELMI. Consistently, GW1929, a selective PPARγ agonist, did not alter mitochondrial function in HCAEC.
Conclusion TELMI upregulates mitochondrial function in human EC through PPARγ independent signaling mechanisms. TELMI could exhibit anti-atherogenic effects through improving mitochondrial dysfunction in EC.