Chymase inhibition prevents fibronectin and myofibrillar loss and improves cardiomyocyte function and LV torsion angle in dogs with isolated mitral regurgitation.
BACKGROUND
The left ventricular (LV) dilatation of isolated mitral regurgitation (MR) is associated with an increase in chymase and a decrease in interstitial collagen and extracellular matrix. In addition to profibrotic effects, chymase has significant antifibrotic actions because it activates matrix metalloproteinases and kallikrein and degrades fibronectin. Thus, we hypothesize that chymase inhibitor (CI) will attenuate extracellular matrix loss and LV remodeling in MR.


RESULTS
We studied dogs with 4 months of untreated MR (MR; n=9) or MR treated with CI (MR+CI; n=8). Cine MRI demonstrated a >40% increase in LV end-diastolic volume in both groups, consistent with a failure of CI to improve a 25% decrease in interstitial collagen in MR. However, LV cardiomyocyte fractional shortening was decreased in MR versus normal dogs (3.71±0.24% versus 4.81±0.31%; P<0.05) and normalized in MR+CI dogs (4.85±0.44%). MRI with tissue tagging demonstrated an increase in LV torsion angle in MR+CI versus MR dogs. CI normalized the significant decrease in fibronectin and FAK phosphorylation and prevented cardiomyocyte myofibrillar degeneration in MR dogs. In addition, total titin and its stiffer isoform were increased in the LV epicardium and paralleled the changes in fibronectin and FAK phosphorylation in MR+CI dogs.


CONCLUSIONS
These results suggest that chymase disrupts cell surface-fibronectin connections and FAK phosphorylation that can adversely affect cardiomyocyte myofibrillar structure and function. The greater effect of CI on epicardial versus endocardial titin and noncollagen cell surface proteins may be responsible for the increase in torsion angle in chronic MR.
Pat
Betty
B
Center for Heart Failure Research, Department of Medicine, University of Alabama at Birmingham, AL 35294-2180, USA.
Chen
Yuanwen
Y
Killingsworth
Cheryl
C
Gladden
James D
JD
Shi
Ke
K
Zheng
Junying
J
Powell
Pamela C
PC
Walcott
Greg
G
Ahmed
Mustafa I
MI
Gupta
Himanshu
H
Desai
Ravi
R
Wei
Chih-Chang
CC
Hase
Naoki
N
Kobayashi
Tsunefumi
T
Sabri
Abdelkarim
A
Granzier
Henk
H
Denney
Thomas
T
Tillson
Michael
M
Dillon
A Ray
AR
Husain
Ahsan
A
Dell'italia
Louis J
LJ
D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D001920:Bradykinin / Q000378:metabolism; D002302:Cardiac Output / Q000502:physiology; D053818:Chymases / Q000037:antagonists & inhibitors*; D003094:Collagen / Q000378:metabolism; D004285:Dogs; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D005353:Fibronectins / Q000378:metabolism*; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D006339:Heart Rate / Q000502:physiology; D008297:Male; D008944:Mitral Valve Insufficiency / Q000378:metabolism / Q000503:physiopathology*; D023421:Models, Animal; D032383:Myocytes, Cardiac / Q000166:cytology / Q000502:physiology*; D009210:Myofibrils / Q000378:metabolism*; D014102:Torsion Abnormality / Q000378:metabolism / Q000503:physiopathology*; D020257:Ventricular Remodeling / Q000502:physiology*
D005353:Fibronectins; D003094:Collagen; D051416:Focal Adhesion Protein-Tyrosine Kinases; D053818:Chymases; D001920:Bradykinin