Chymase inhibition prevents fibronectin and myofibrillar loss and improves cardiomyocyte function and LV torsion angle in dogs with isolated mitral regurgitation

Betty Pat, Yuanwen Chen, Cheryl Killingsworth, James D. Gladden, Ke Shi, Junying Zheng, Pamela C. Powell, Greg Walcott, Mustafa I. Ahmed, Himanshu Gupta, Ravi Desai, Chih Chang Wei, Naoki Hase, Tsunefumi Kobayashi, Abdelkarim Sabri, Hendrikus "Henk" Granzier, Thomas Denney, Michael Tillson, A. Ray Dillon, Ahsan Husain & 1 others Louis J. Dell'Italia

Research output: Contribution to journalArticle

35 Citations (Scopus)

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. Methods and 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.

Original languageEnglish (US)
Pages (from-to)1488-1495
Number of pages8
JournalCirculation
Volume122
Issue number15
DOIs
StatePublished - Oct 12 2010

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Chymases
Mitral Valve Insufficiency
Left Ventricular Function
Fibronectins
Cardiac Myocytes
Dogs
Connectin
Phosphorylation
Extracellular Matrix
Collagen
Cine Magnetic Resonance Imaging
Kallikreins
Ventricular Remodeling
Pericardium
Matrix Metalloproteinases

Keywords

  • cardiac volume
  • collagen
  • heart contractility
  • heart failure
  • mitral valve

ASJC Scopus subject areas

  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine
  • Medicine(all)

Cite this

Chymase inhibition prevents fibronectin and myofibrillar loss and improves cardiomyocyte function and LV torsion angle in dogs with isolated mitral regurgitation. / Pat, Betty; Chen, Yuanwen; Killingsworth, Cheryl; Gladden, James D.; Shi, Ke; Zheng, Junying; Powell, Pamela C.; Walcott, Greg; Ahmed, Mustafa I.; Gupta, Himanshu; Desai, Ravi; Wei, Chih Chang; Hase, Naoki; Kobayashi, Tsunefumi; Sabri, Abdelkarim; Granzier, Hendrikus "Henk"; Denney, Thomas; Tillson, Michael; Dillon, A. Ray; Husain, Ahsan; Dell'Italia, Louis J.

In: Circulation, Vol. 122, No. 15, 12.10.2010, p. 1488-1495.

Research output: Contribution to journalArticle

Pat, B, Chen, Y, Killingsworth, C, Gladden, JD, Shi, K, Zheng, J, Powell, PC, Walcott, G, Ahmed, MI, Gupta, H, Desai, R, Wei, CC, Hase, N, Kobayashi, T, Sabri, A, Granzier, HH, Denney, T, Tillson, M, Dillon, AR, Husain, A & Dell'Italia, LJ 2010, 'Chymase inhibition prevents fibronectin and myofibrillar loss and improves cardiomyocyte function and LV torsion angle in dogs with isolated mitral regurgitation', Circulation, vol. 122, no. 15, pp. 1488-1495. https://doi.org/10.1161/CIRCULATIONAHA.109.921619
Pat, Betty ; Chen, Yuanwen ; Killingsworth, Cheryl ; Gladden, James D. ; Shi, Ke ; Zheng, Junying ; Powell, Pamela C. ; Walcott, Greg ; Ahmed, Mustafa I. ; Gupta, Himanshu ; Desai, Ravi ; Wei, Chih Chang ; Hase, Naoki ; Kobayashi, Tsunefumi ; Sabri, Abdelkarim ; Granzier, Hendrikus "Henk" ; Denney, Thomas ; Tillson, Michael ; Dillon, A. Ray ; Husain, Ahsan ; Dell'Italia, Louis J. / Chymase inhibition prevents fibronectin and myofibrillar loss and improves cardiomyocyte function and LV torsion angle in dogs with isolated mitral regurgitation. In: Circulation. 2010 ; Vol. 122, No. 15. pp. 1488-1495.
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T1 - Chymase inhibition prevents fibronectin and myofibrillar loss and improves cardiomyocyte function and LV torsion angle in dogs with isolated mitral regurgitation

AU - Pat, Betty

AU - Chen, Yuanwen

AU - Killingsworth, Cheryl

AU - Gladden, James D.

AU - Shi, Ke

AU - Zheng, Junying

AU - Powell, Pamela C.

AU - Walcott, Greg

AU - Ahmed, Mustafa I.

AU - Gupta, Himanshu

AU - Desai, Ravi

AU - Wei, Chih Chang

AU - Hase, Naoki

AU - Kobayashi, Tsunefumi

AU - Sabri, Abdelkarim

AU - Granzier, Hendrikus "Henk"

AU - Denney, Thomas

AU - Tillson, Michael

AU - Dillon, A. Ray

AU - Husain, Ahsan

AU - Dell'Italia, Louis J.

PY - 2010/10/12

Y1 - 2010/10/12

N2 - 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. Methods and 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.

AB - 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. Methods and 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.

KW - cardiac volume

KW - collagen

KW - heart contractility

KW - heart failure

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