Renin Overexpression Leads to Increased Titin‐Based Stiffness Contributing to Diastolic Dysfunction in Hypertensive mRen2 Rats

Abstract

Hypertension is a major risk factor for heart failure (HF). We investigated the influence of hypertension on cardiac contraction and relaxation in transgenic renin overexpressing rats (carrying mouse Ren‐2 renin gene, mRen2, n=6). Blood pressure (BP) was measured by tail‐cuff method, echocardiography was used to characterize cardiac contractility, cellular force measurements and biochemical assays were applied to reveal molecular mechanisms. Sprague‐Dawley (SD) rats (n=6) were used as control. 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). No effects of transgenic renin expression on systolic parameters, such as LV ejection fraction (EF, 68.50±2.09 vs. 70.17±1.45 % in SD), maximal Ca2+‐activated force (25.89±0.99 vs. 29.05±2.80 kN/m2 in SD) and Ca2+‐sensitivity of force production (pCa50, 5.83±0.01 vs. 5.87±0.05 in SD) were found. In contrast, pronounced diastolic dysfunction (DD) was observed in mRen2 rats: ratio of peak early and late LV diastolic filling (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) and cardiomyocyte passive stiffness was higher (1.74±0.06 vs. 1.28±0.18 kN/m2, P<0.05), compared to SD, respectively. Finally, hyperphosphorylation of titin at Ser‐12742 within the PEVK domain (P<0.05) proposed a molecular mechanism for DD. 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 DD. Accordingly, mRen2 rat might provide an in vivo model for HF with preserved EF (HFpEF).Support or Funding InformationThis work was supported by a European Union FP7 grant (MEDIA: metabolic road to diastolic heart failure) and by the Hungarian Scientific Research Fund (K116940 and K109083).