Abstract 12553: Telmisartan, a Clinically Available Anti-Hypertensive Medicine, Enhances Mitochondrial Function and Improves Endothelial Dysfunction Through the AMPK Pathway

Abstract

Background: Mitochondrial dysfunction plays an important role in cellular senescence and impaired function of vascular endothelium, resulted in cardiovascular diseases. AMP-activated protein kinase (AMPK) plays a critical role in mitochondrial biogenesis and endothelial function. Telmisartan (TELMI) is a unique angiotensin II type I receptor blocker (ARB) that has clinically been shown to prevent cardiovascular events in high risk patients. We investigated whether TELMI could modulate mitochondrial function leads to improvement of endothelial function via AMPK, and could improve endothelial function in mice and human. Methods and Results: In cultured human coronary artery endothelial cells (HCAECs), TELMI significantly increased the phosphorylation of AMPK (1.61±0.45 fold, p<0.05) and endothelial nitric oxide synthase (eNOS) (1.39±0.23 fold, p<0.01), and enhanced mitochondrial function as assessed by both mitochondrial reductase activity (1.22±0.15 fold, p<0.01) and ATP production (1.16±0.93 fold, p<0.05). TELMI prevented cellular senescence (senescence associated β-galactosidase staining assay: 0.61±0.14 fold, p<0.01) and enhanced angiogenic activity (tubular formation: 1.73±0.25 fold, p<0.01). These effects by TELMI were abolished by both pharmacological and genetical inhibition of AMPK. In a mouse model of metabolic syndrome, TELMI prevented high fat diet (HFD)-induced endothelial dysfunction, as shown by acetylcholine-induced vascular relaxation (HFD: 74.5±3.3%, HFD+TELMI: 84.8±3.2% P<0.05), and increased the phosphorylation of AMPK (1.28±0.13 fold, P<0.05) and eNOS (1.27±0.16 fold, P<0.05) in aortas. In hypertensive patients, switching treatment from other ARB or angiotensin converting enzyme inhibitors to TELMI improved endothelial function assessed by reactive hyperemia on peripheral arterial tonometry index (pre-TELMI: 0.40±0.14, post-TELMI 0.54±0.17, p<0.05). Conclusions: TELMI significantly enhanced mitochondrial function and exhibited anti-senescent activity via AMPK in HCAECs, and improved endothelial function in mice and human. The vascular protective effects induced by TELMI may partly be due to its enhancement of mitochondrial function and reduction of endothelial senescence by AMPK.