PMID- 25595602
OWN - NLM
STAT- MEDLINE
DCOM- 20160205
LR  - 20181202
IS  - 1432-1440 (Electronic)
IS  - 0946-2716 (Linking)
VI  - 93
IP  - 6
DP  - 2015 Jun
TI  - Carvedilol improves biventricular fibrosis and function in experimental pulmonary 
      hypertension.
PG  - 663-74
LID - 10.1007/s00109-015-1251-9 [doi]
AB  - Left ventricular (LV) function influences outcomes in right ventricular (RV) 
      failure. Carvedilol reduces mortality in LV failure and improves RV function in 
      experimental pulmonary arterial hypertension (PAH). However, its impact on 
      ventricular-ventricular interactions and LV function in RV afterload is unknown. 
      We investigated effects of carvedilol on biventricular fibrosis and function in a 
      rat model of persistent PAH. Rats were randomized into three groups: Sham 
      controls, PAH, and PAH + carvedilol. Severe PAH was induced by 60 mg/kg 
      subcutaneous monocrotaline. In the treatment group, oral carvedilol (15 
      mg/kg/day) was started 2 weeks after monocrotaline injection and continued for 3 
      weeks until the terminal experiment. Echocardiography and exercise performance 
      were performed at baseline and repeated at the terminal experiment with 
      hemodynamic measurements. LV and RV myocardium were analyzed for hypertrophy, 
      fibrosis, and molecular signaling by protein and mRNA analysis. PAH and 
      PAH + carvedilol rats experienced severely elevated pulmonary arterial pressures 
      and RV hypertrophy. Despite similar RV systolic pressures, carvedilol reduced 
      biventricular collagen content (RV fibrosis area; 13.4 +/- 6.5 vs. 5.5 +/- 2.7 %, 
      p < 0.001) and expression of transforming growth factor-beta1 (TGFbeta1) (RV 
      TGFbeta1/glyceraldehyde 3-phosphate dehydrogenase (GAPDH) ratio; 1.16 +/- 0.39 vs. 
      0.57 +/- 0.22, p < 0.01) and connective tissue growth factor (CTGF) (RV CTGF/GAPDH 
      ratio; 0.49 +/- 0.06 vs. 0.35 +/- 0.17, p < 0.05). RV pro-apoptotic caspase-8 was 
      increased in PAH compared to controls and was significantly reduced in both 
      ventricles compared to PAH animals by carvedilol. Tissue effects were accompanied 
      by improved biventricular systolic and diastolic performance and exercise 
      treadmill distance (36 +/- 30 vs. 80 +/- 33 m, p < 0.05). In RV pressure-load, 
      carvedilol improves biventricular fibrosis and function through abrogation of 
      TGFbeta1-CTGF signaling. KEY MESSAGE: * RV afterload caused biventricular injury and 
      dysfunction through TGFbeta1-CTGF signaling. * Carvedilol reduced biventricular 
      TGFbeta1-CTGF signaling, fibrosis, and apoptosis. * Carvedilol improved cardiac 
      output and biventricular function. * Improved fibrosis and hemodynamics occurred 
      despite persistent RV afterload.
FAU - Okumura, Kenichi
AU  - Okumura K
AD  - The Labatt Family Heart Center, Division of Cardiology and Cardiovascular 
      Surgery, Hospital for Sick Children and University of Toronto, Toronto, ON, 
      Canada.
FAU - Kato, Hideyuki
AU  - Kato H
FAU - Honjo, Osami
AU  - Honjo O
FAU - Breitling, Siegfried
AU  - Breitling S
FAU - Kuebler, Wolfgang M
AU  - Kuebler WM
FAU - Sun, Mei
AU  - Sun M
FAU - Friedberg, Mark K
AU  - Friedberg MK
LA  - eng
GR  - Canadian Institutes of Health Research/Canada
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20150118
PL  - Germany
TA  - J Mol Med (Berl)
JT  - Journal of molecular medicine (Berlin, Germany)
JID - 9504370
RN  - 0 (Antihypertensive Agents)
RN  - 0 (Carbazoles)
RN  - 0 (Propanolamines)
RN  - 0 (Transforming Growth Factor beta1)
RN  - 0K47UL67F2 (Carvedilol)
RN  - 139568-91-5 (Connective Tissue Growth Factor)
SB  - IM
MH  - Animals
MH  - Antihypertensive Agents/*therapeutic use
MH  - Carbazoles/*therapeutic use
MH  - Carvedilol
MH  - Connective Tissue Growth Factor/metabolism
MH  - Fibrosis
MH  - Heart Ventricles/*drug effects/metabolism/pathology/*physiopathology
MH  - Hemodynamics/drug effects
MH  - Hypertension, Pulmonary/*drug therapy/metabolism/pathology/physiopathology
MH  - Male
MH  - Propanolamines/*therapeutic use
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Signal Transduction/drug effects
MH  - Transforming Growth Factor beta1/metabolism
MH  - Ventricular Dysfunction, Right/*drug therapy/metabolism/pathology/physiopathology
EDAT- 2015/01/18 06:00
MHDA- 2016/02/06 06:00
CRDT- 2015/01/18 06:00
PHST- 2014/07/23 00:00 [received]
PHST- 2015/01/06 00:00 [accepted]
PHST- 2014/12/15 00:00 [revised]
PHST- 2015/01/18 06:00 [entrez]
PHST- 2015/01/18 06:00 [pubmed]
PHST- 2016/02/06 06:00 [medline]
AID - 10.1007/s00109-015-1251-9 [doi]
PST - ppublish
SO  - J Mol Med (Berl). 2015 Jun;93(6):663-74. doi: 10.1007/s00109-015-1251-9. Epub 
      2015 Jan 18.