Abstract 538: Overexpression of the Catalytic Subunit of Telomerase Protects Against Ang II Induced Vascular Dysfunction
Rational: Angiotensin II (A II) produces endothelial dysfunction by elevating vascular reactive oxygen species (ROS) production from mitochondria. Telomerase, prominent in cellular senescence and tissue aging, reduces mitochondrial ROS production. Conversely, loss of the catalytic subunit of telomerase (TERT-/-) causes hypertension and reduced NO bioavailability. We have shown previously that decreased TERT abrogates NO mediated dilation and increases mtROS levels.
We hypothesized that overexpression of TERT attenuates A II induced endothelial dysfunction by suppressing ROS production, while loss of TERT predisposes to A II induced endothelial dysfunction.
Results: Mouse mesenteric arterioles (~250 μm) from hTERT transgenic, TERT-/- and control mice were infused with A II (via osmotic mini pump, 2 weeks) were used. Flow-mediated dilation (FMD) to graded degrees of shear was measured in vessels constricted with norepinephrine.
A II (400ng/kg/min) reduced FMD in TERT-/- but not in WT controls (left). The mechanism of FMD was changed in TERT-/- from NO to H2O2 as previously shown. TERT transgenic mice showed hyper relaxation to shear which was normalized by A II treatment (1000ng/kg/min), while in WT control animals the same dose of A II reduced endothelium-dependent dilation (right).
Conclusions: We conclude that up-regulation of TERT is sufficient to prevent A II mediated endothelial dysfunction, likely by suppressing ROS formation and preserving physiological NO levels in the microvascular.
Author Disclosures: J. Hockenberry: None. D.D. Gutterman: None. A.M. Beyer: None.
- © 2014 by American Heart Association, Inc.