Abstract 12547: Telmisartan Enhances Mitochondrial Biogenesis and Protects Endothelial Cells from Oxidative Injury Through AMP-Activated Protein Kinase
Background Mitochondrial dysfunction in endothelium might be involved in atherogenesis. Telmisartan (TELMI), which is effective for hypertension and metabolic disorder, reduced cardiovascular events in high risk patients. Adenosine monophosphate activated kinase (AMPK) plays a critical role in cellular energy adaptation, implicating AMPK might be a key regulator of endothelial dysfunction.
Methods and Results Mitochondrial mass in human coronary artery endothelial cells (HCAEC) decreased as a result of endothelial dysfunction induced by TNFα exposure (0.90±0.07 fold vs. vehicle, p<0.01). TELMI increased mitochondrial mass of HCAEC as assessed by MitoTracker Green (1.18±0.07 fold, p<0.01) and preserved mitochondrial mass from TNFα exposure (TNFα+TELMI 1.08±0.11 fold, p<0.01). Moreover, TELMI enhanced HCAEC mitochondrial function as assessed by colorimetric mitochondrial NAD(P)H assay, in a time and concentration dependent manner (0–48 hours, 0.1–10μM, up to 1.9±0.1 fold, p<0.01), but other sartans did not have the similar effects. Messenger RNA expression levels of TFAM, manganese SOD, glutathione peroxide, and mitochondrial DNA were significantly increased in HCAEC after 48 hours TELMI treatment (1.20±0.04, 1.32±0.04, 1.13±0.07, 1.31±0.10 fold, respectively, p<0.05). Western blots demonstrated TELMI enhanced AMPK phosphorylation (TELMI 1.61±0.4 fold, p<0.05) and this effect was prevented by selective AMPK blocker, Compound C (TELMI+Compound C 0.74±0.8 fold, p<0.01). Inhibition of AMPK by Compound C lost increased mitochondria biogenesis induced by TELMI (TELMI+Compound C 0.83±0.04 fold, p<0.01). TELMI could increase mitochondrial function even in HCAEC that PPARγ was depleted by siRNA (1.61±0.44 fold, p<0.01). Pretreatment of HCAEC with TELMI preserved the mitochondrial function from 1.0mM H2O2 exposure assessed by NAD(P)H levels (1.3±0.2 fold, p<0.01), and also reduced apoptotic annexin V positive HCAEC induced by 100μM H2O2 (% apoptosis EC: vehicle 38.3±3.1%, TELMI 26.0±2.3, p<0.01).
Conclusion TELMI upregulates mitochondrial function in HCAEC through activation of AMPK, but not PPARγ, signaling pathway. TELMI could exhibit anti-atherogenic effects through improving mitochondrial dysfunction in endothelium.
- © 2010 by American Heart Association, Inc.