Renin overexpression leads to increased titin-based stiffness contributing to diastolic dysfunction in hypertensive mRen2 rats

Árpád Kovács, Gábor Fülöp, Andrea Kovács, Tamás Csípő, Beáta Bódi, Dániel Priksz, B. Juhász, Lívia Beke, Zoltán Hendrik, G. Méhes, Henk L. Granzier, I. Édes, Miklós Fagyas, Z. Papp, Judit Barta, Attila Tóth

Research output: Contribution to journalArticle

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Abstract

Hypertension (HTN) is a major risk factor for heart failure. We investigated the influence of HTN on cardiac contraction and relaxation in transgenic renin overexpressing rats (carrying mouse Ren-2 renin gene, mRen2, n = 6). Blood pressure (BP) was measured. Cardiac contractility was characterized by echocardiography, cellular force measurements, and biochemical assays were applied to reveal molecular mechanisms. Sprague-Dawley (SD) rats (n = 6) were used as controls. Transgenic rats had higher circulating renin activity and lower cardiac angiotensin-converting enzyme two levels. Systolic BP was elevated in mRen2 rats (235.11 ± 5.32 vs. 127.03 ± 7.56 mmHg in SD, P < 0.05), resulting in increased left ventricular (LV) weight/body weight ratio (4.05 ± 0.09 vs. 2.77 ± 0.08 mg/g in SD, P < 0.05). Transgenic renin expression had no effect on the systolic parameters, such as LV ejection fraction, cardiomyocyte Ca2+-activated force, and Ca2+ sensitivity of force production. In contrast, diastolic dysfunction was observed in mRen2 compared with SD rats: early and late LV diastolic filling ratio (E/A) was lower (1.14 ± 0.04 vs. 1.87 ± 0.08, P < 0.05), LV isovolumetric relaxation time was longer (43.85 ± 0.89 vs. 28.55 ± 1.33 ms, P < 0.05), cardiomyocyte passive tension was higher (1.74 ± 0.06 vs. 1.28 ± 0.18 kN/m2, P < 0.05), and lung weight/body weight ratio was increased (6.47 ± 0.24 vs. 5.78 ± 0.19 mg/g, P < 0.05), as was left atrial weight/body weight ratio (0.21 ± 0.03 vs. 0.14 ± 0.03 mg/g, P < 0.05). Hyperphosphorylation of titin at Ser-12742 within the PEVK domain and a twofold overexpression of protein kinase C-α in mRen2 rats were detected. Our data suggest a link between the activation of renin-angiotensin-aldosterone system and increased titin-based stiffness through phosphorylation of titin's PEVK element, contributing to diastolic dysfunction.

Original languageEnglish
Pages (from-to)H1671-H1682
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume310
Issue number11
DOIs
Publication statusPublished - Jun 1 2016

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Connectin
Renin
Body Weight
Blood Pressure
Cardiac Myocytes
Weights and Measures
Sprague Dawley Rats
Transgenic Rats
Hypertension
Peptidyl-Dipeptidase A
Renin-Angiotensin System
Stroke Volume
Protein Kinase C
Echocardiography
Heart Failure
Phosphorylation
Lung
Genes

Keywords

  • Diastolic dysfunction
  • Hypertension
  • Passive stiffness
  • RAAS
  • Renin-angiotensin-aldosterone system
  • Titin phosphorylation

ASJC Scopus subject areas

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

Cite this

Renin overexpression leads to increased titin-based stiffness contributing to diastolic dysfunction in hypertensive mRen2 rats. / Kovács, Árpád; Fülöp, Gábor; Kovács, Andrea; Csípő, Tamás; Bódi, Beáta; Priksz, Dániel; Juhász, B.; Beke, Lívia; Hendrik, Zoltán; Méhes, G.; Granzier, Henk L.; Édes, I.; Fagyas, Miklós; Papp, Z.; Barta, Judit; Tóth, Attila.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 310, No. 11, 01.06.2016, p. H1671-H1682.

Research output: Contribution to journalArticle

Kovács, Árpád ; Fülöp, Gábor ; Kovács, Andrea ; Csípő, Tamás ; Bódi, Beáta ; Priksz, Dániel ; Juhász, B. ; Beke, Lívia ; Hendrik, Zoltán ; Méhes, G. ; Granzier, Henk L. ; Édes, I. ; Fagyas, Miklós ; Papp, Z. ; Barta, Judit ; Tóth, Attila. / Renin overexpression leads to increased titin-based stiffness contributing to diastolic dysfunction in hypertensive mRen2 rats. In: American Journal of Physiology - Heart and Circulatory Physiology. 2016 ; Vol. 310, No. 11. pp. H1671-H1682.
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AU - Kovács, Árpád

AU - Fülöp, Gábor

AU - Kovács, Andrea

AU - Csípő, Tamás

AU - Bódi, Beáta

AU - Priksz, Dániel

AU - Juhász, B.

AU - Beke, Lívia

AU - Hendrik, Zoltán

AU - Méhes, G.

AU - Granzier, Henk L.

AU - Édes, I.

AU - Fagyas, Miklós

AU - Papp, Z.

AU - Barta, Judit

AU - Tóth, Attila

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N2 - Hypertension (HTN) is a major risk factor for heart failure. We investigated the influence of HTN on cardiac contraction and relaxation in transgenic renin overexpressing rats (carrying mouse Ren-2 renin gene, mRen2, n = 6). Blood pressure (BP) was measured. Cardiac contractility was characterized by echocardiography, cellular force measurements, and biochemical assays were applied to reveal molecular mechanisms. Sprague-Dawley (SD) rats (n = 6) were used as controls. Transgenic rats had higher circulating renin activity and lower cardiac angiotensin-converting enzyme two levels. Systolic BP was elevated in mRen2 rats (235.11 ± 5.32 vs. 127.03 ± 7.56 mmHg in SD, P < 0.05), resulting in increased left ventricular (LV) weight/body weight ratio (4.05 ± 0.09 vs. 2.77 ± 0.08 mg/g in SD, P < 0.05). Transgenic renin expression had no effect on the systolic parameters, such as LV ejection fraction, cardiomyocyte Ca2+-activated force, and Ca2+ sensitivity of force production. In contrast, diastolic dysfunction was observed in mRen2 compared with SD rats: early and late LV diastolic filling ratio (E/A) was lower (1.14 ± 0.04 vs. 1.87 ± 0.08, P < 0.05), LV isovolumetric relaxation time was longer (43.85 ± 0.89 vs. 28.55 ± 1.33 ms, P < 0.05), cardiomyocyte passive tension was higher (1.74 ± 0.06 vs. 1.28 ± 0.18 kN/m2, P < 0.05), and lung weight/body weight ratio was increased (6.47 ± 0.24 vs. 5.78 ± 0.19 mg/g, P < 0.05), as was left atrial weight/body weight ratio (0.21 ± 0.03 vs. 0.14 ± 0.03 mg/g, P < 0.05). Hyperphosphorylation of titin at Ser-12742 within the PEVK domain and a twofold overexpression of protein kinase C-α in mRen2 rats were detected. Our data suggest a link between the activation of renin-angiotensin-aldosterone system and increased titin-based stiffness through phosphorylation of titin's PEVK element, contributing to diastolic dysfunction.

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KW - RAAS

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