title: Chymase inhibition prevents fibronectin and myofibrillar loss and improves cardiomyocyte function and LV torsion angle in dogs with isolated mitral regurgitation.
abstract: 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.
authors.affiliation: Center for Heart Failure Research, Department of Medicine, University of Alabama at Birmingham, AL 35294-2180, USA.
authors.forename: Betty
authors.initials: B
authors.lastname: Pat
authors.forename: Yuanwen
authors.initials: Y
authors.lastname: Chen
authors.forename: Cheryl
authors.initials: C
authors.lastname: Killingsworth
authors.forename: James D
authors.initials: JD
authors.lastname: Gladden
authors.forename: Ke
authors.initials: K
authors.lastname: Shi
authors.forename: Junying
authors.initials: J
authors.lastname: Zheng
authors.forename: Pamela C
authors.initials: PC
authors.lastname: Powell
authors.forename: Greg
authors.initials: G
authors.lastname: Walcott
authors.forename: Mustafa I
authors.initials: MI
authors.lastname: Ahmed
authors.forename: Himanshu
authors.initials: H
authors.lastname: Gupta
authors.forename: Ravi
authors.initials: R
authors.lastname: Desai
authors.forename: Chih-Chang
authors.initials: CC
authors.lastname: Wei
authors.forename: Naoki
authors.initials: N
authors.lastname: Hase
authors.forename: Tsunefumi
authors.initials: T
authors.lastname: Kobayashi
authors.forename: Abdelkarim
authors.initials: A
authors.lastname: Sabri
authors.forename: Henk
authors.initials: H
authors.lastname: Granzier
authors.forename: Thomas
authors.initials: T
authors.lastname: Denney
authors.forename: Michael
authors.initials: M
authors.lastname: Tillson
authors.forename: A Ray
authors.initials: AR
authors.lastname: Dillon
authors.forename: Ahsan
authors.initials: A
authors.lastname: Husain
authors.forename: Louis J
authors.initials: LJ
authors.lastname: Dell'italia
mesh_terms: 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*
chemical_list: D005353:Fibronectins; D003094:Collagen; D051416:Focal Adhesion Protein-Tyrosine Kinases; D053818:Chymases; D001920:Bradykinin