title: Renin overexpression leads to increased titin-based stiffness contributing to diastolic dysfunction in hypertensive mRen2 rats.
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 Ca(2+)-activated force, and Ca(2+) 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/m(2), 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.
authors.affiliation: Division of Clinical Physiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary;
authors.forename: Árpád
authors.initials: Á
authors.lastname: Kovács
authors.affiliation: Division of Clinical Physiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary;
authors.forename: Gábor Á
authors.initials: GÁ
authors.lastname: Fülöp
authors.affiliation: Division of Clinical Physiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary;
authors.forename: Andrea
authors.initials: A
authors.lastname: Kovács
authors.affiliation: Division of Clinical Physiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary;
authors.forename: Tamás
authors.initials: T
authors.lastname: Csípő
authors.affiliation: Division of Clinical Physiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary;
authors.forename: Beáta
authors.initials: B
authors.lastname: Bódi
authors.affiliation: Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Debrecen, Debrecen, Hungary;
authors.forename: Dániel
authors.initials: D
authors.lastname: Priksz
authors.affiliation: Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Debrecen, Debrecen, Hungary;
authors.forename: Béla
authors.initials: B
authors.lastname: Juhász
authors.affiliation: Department of Pathology, Medical Center, University of Debrecen, Debrecen, Hungary;
authors.forename: Lívia
authors.initials: L
authors.lastname: Beke
authors.affiliation: Department of Pathology, Medical Center, University of Debrecen, Debrecen, Hungary;
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Hendrik
authors.affiliation: Department of Pathology, Medical Center, University of Debrecen, Debrecen, Hungary;
authors.forename: Gábor
authors.initials: G
authors.lastname: Méhes
authors.affiliation: Department of Physiology, University of Arizona, Tucson, Arizona; and.
authors.forename: Henk L
authors.initials: HL
authors.lastname: Granzier
authors.affiliation: Department of Cardiology, Medical Center, University of Debrecen, Debrecen, Hungary; Research Center for Molecular Medicine, University of Debrecen, Debrecen, Hungary.
authors.forename: István
authors.initials: I
authors.lastname: Édes
authors.affiliation: Division of Clinical Physiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary; Department of Cardiology, Medical Center, University of Debrecen, Debrecen, Hungary;
authors.forename: Miklós
authors.initials: M
authors.lastname: Fagyas
authors.affiliation: Division of Clinical Physiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary; Research Center for Molecular Medicine, University of Debrecen, Debrecen, Hungary.
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Papp
authors.affiliation: Department of Cardiology, Medical Center, University of Debrecen, Debrecen, Hungary; bartajud@gmail.com.
authors.forename: Judit
authors.initials: J
authors.lastname: Barta
authors.affiliation: Division of Clinical Physiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary; Research Center for Molecular Medicine, University of Debrecen, Debrecen, Hungary.
authors.forename: Attila
authors.initials: A
authors.lastname: Tóth
mesh_terms: D000818:Animals; D064211:Connectin / Q000378:metabolism*; D006973:Hypertension / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D012083:Renin / Q000235:genetics / Q000378:metabolism*; D012084:Renin-Angiotensin System / Q000502:physiology*; D018754:Ventricular Dysfunction / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology
chemical_list: D064211:Connectin; D012083:Renin
keywords: RAAS; diastolic dysfunction; hypertension; passive stiffness; renin-angiotensin-aldosterone system; titin phosphorylation