当前位置： SCI文献检索 > CIRCULATION期刊下所有文献 > Reversal of global apoptosis and regional stress kinase activation by cardiac resynchronization.

Reversal of global apoptosis and regional stress kinase activation by cardiac resynchronization.

Abstract：

BACKGROUND:Cardiac dyssynchrony in the failing heart worsens global function and efficiency and generates regional loading disparities that may exacerbate stress-response molecular signaling and worsen cell survival. We hypothesized that cardiac resynchronization (CRT) from biventricular stimulation reverses such molecular abnormalities at the regional and global levels. METHODS AND RESULTS:Adult dogs (n=27) underwent left bundle-branch radiofrequency ablation, prolonging the QRS by 100%. Dogs were first subjected to 3 weeks of atrial tachypacing (200 bpm) to induce dyssynchronous heart failure (DHF) and then randomized to either 3 weeks of additional atrial tachypacing (DHF) or biventricular tachypacing (CRT). At 6 weeks, ejection fraction improved in CRT (2.8+/-1.8%) compared with DHF (-4.4+/-2.7; P=0.02 versus CRT) dogs, although both groups remained in failure with similarly elevated diastolic pressures and reduced dP/dtmax. In DHF, mitogen-activated kinase p38 and calcium-calmodulin-dependent kinase were disproportionally expressed/activated (50% to 150%), and tumor necrosis factor-alpha increased in the late-contracting (higher-stress) lateral versus septal wall. These disparities were absent with CRT. Apoptosis assessed by terminal deoxynucleotide transferase-mediated dUTP nick-end labeling staining, caspase-3 activity, and nuclear poly ADP-ribose polymerase cleavage was less in CRT than DHF hearts and was accompanied by increased Akt phosphorylation/activity. Bcl-2 and BAD protein diminished with DHF but were restored by CRT, accompanied by marked BAD phosphorylation, enhanced BAD-14-3-3 interaction, and reduced phosphatase PP1alpha, consistent with antiapoptotic effects. Other Akt-coupled modulators of apoptosis (FOXO-3alpha and GSK3beta) were more phosphorylated in DHF than CRT and thus less involved. CONCLUSIONS:CRT reverses regional and global molecular remodeling, generating more homogeneous activation of stress kinases and reducing apoptosis. Such changes are important benefits from CRT that likely improve cardiac performance and outcome.

journal_name

Circulation

journal_title

Circulation

authors

Chakir K,Daya SK,Tunin RS,Helm RH,Byrne MJ,Dimaano VL,Lardo AC,Abraham TP,Tomaselli GF,Kass DA

doi

10.1161/CIRCULATIONAHA.107.706291

subject

Has Abstract

pub_date

2008-03-18 00:00:00

pages

1369-77

issue

eissn

0009-7322

issn

1524-4539

pii

CIRCULATIONAHA.107.706291

journal_volume

117

pub_type

杂志文章

在线工具

Reversal of global apoptosis and regional stress kinase activation by cardiac resynchronization.