Critical Role for Telomerase in the Mechanism of Flow-Mediated Dilation in the Human Microcirculation

被引：87

作者：

Beyer, Andreas M. ^{[1
,2
]}

Freed, Julie K.

Durand, Matthew J. ^{[1
,3
]}

Riedel, Michael ^{[1
]}

Ait-Aissa, Karima ^{[1
,2
]}

Green, Paula ^{[5
]}

Hockenberry, Joseph C. ^{[1
]}

Morgan, R. Garret ^{[6
]}

Donato, Anthony J. ^{[6
]}

Peleg, Refael ^{[7
]}

Gasparri, Mario ^{[4
]}

Rokkas, Chris K. ^{[4
]}

Santos, Janine H. ^{[5
]}

Priel, Esther ^{[7
]}

Gutterman, David D. ^{[1
,2
]}

机构：

[1] Med Coll Wisconsin, Dept Med, Cardiovasc Ctr, Milwaukee, WI 53226 USA

[2] Med Coll Wisconsin, Dept Physiol, 8701 Watertown Plank Rd, Milwaukee, WI 53226 USA

[3] Med Coll Wisconsin, Dept Phys Med & Rehabil, Milwaukee, WI 53226 USA

[4] Med Coll Wisconsin, Dept Surg, Cardiothorac Surg, 8700 W Wisconsin Ave, Milwaukee, WI 53226 USA

[5] New Jersey Med Sch Rutgers, Dept Physiol & Pharmacol, Newark, NJ USA

[6] Univ Utah, Sch Med, Dept Internal Med, Salt Lake City, UT USA

[7] Ben Gurion Univ Negev, Fac Hlth Sci, Shraga Segal Dept Immunol & Microbiol, Beer Sheva, Israel

来源：

CIRCULATION RESEARCH | 2016年 / 118卷 / 05期

基金：

美国国家卫生研究院;

关键词：

vascular biology; microvascular dysfunction; telomerase activity; coronary artery disease; flow-mediated dilation; mitochondria; reactive oxygen species; HUMAN CORONARY ARTERIOLES; ENDOTHELIAL-CELL SENESCENCE; SMOOTH-MUSCLE-CELLS; HYDROGEN-PEROXIDE; REVERSE-TRANSCRIPTASE; NITRIC-OXIDE; OXIDATIVE STRESS; MITOCHONDRIAL DYSFUNCTION; DEPENDENT DILATION; DNA-DAMAGE;

D O I：

10.1161/CIRCRESAHA.115.307918

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Rationale: Telomerase is a nuclear regulator of telomere elongation with recent reports suggesting a role in regulation of mitochondrial reactive oxygen species. Flow-mediated dilation in patients with cardiovascular disease is dependent on the formation of reactive oxygen species. Objective: We examined the hypothesis that telomerase activity modulates microvascular flow-mediated dilation, and loss of telomerase activity contributes to the change of mediator from nitric oxide to mitochondrial hydrogen peroxide in patients with coronary artery disease (CAD). Methods and Results: Human coronary and adipose arterioles were isolated for videomicroscopy. Flow-mediated dilation was measured in vessels pretreated with the telomerase inhibitor BIBR-1532 or vehicle. Statistical differences between groups were determined using a 2-way analysis of variance repeated measure (n >= 4; P < 0.05). L-NAME (N-omega-nitro-L-arginine methyl ester; nitric oxide synthase inhibitor) abolished flow-mediated dilation in arterioles from subjects without CAD, whereas polyethylene glycol-catalase (PEG-catalase; hydrogen peroxide scavenger) had no effect. After exposure to BIBR-1532, arterioles from non-CAD subjects maintained the magnitude of dilation but changed the mediator from nitric oxide to mitochondrial hydrogen peroxide (% max diameter at 100 cm H2O: vehicle 74.6 +/- 4.1, L-NAME 37.0 +/- 2.0*, PEG-catalase 82.1 +/- 2.8; BIBR-1532 69.9 +/- 4.0, L-NAME 84.7 +/- 2.2, PEG-catalase 36.5 +/- 6.9*). Conversely, treatment of microvessels from CAD patients with the telomerase activator AGS 499 converted the PEG-catalase-inhibitable dilation to one mediated by nitric oxide (% max diameter at 100 cm H2O: adipose, AGS 499 78.5 +/- 3.9; L-NAME 10.9 +/- 17.5*; PEG-catalase 79.2 +/- 4.9). Endothelial-independent dilation was not altered with either treatment. Conclusions: We have identified a novel role for telomerase in re-establishing a physiological mechanism of vasodilation in arterioles from subjects with CAD. These findings suggest a new target for reducing the oxidative milieu in the microvasculature of patients with CAD.

引用

页码：856 / 866

页数：11

共 65 条

[1] Telomerase does not counteract telomere shortening but protects mitochondrial function under oxidative stress [J].