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 2 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 (DD) was observed in mRen2 when compared to 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), lung weight/body weight ratio was increased (6.47±0.24 vs. 5.78±0.19 mg/g, P<0.05), alike 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 two-fold overexpression of protein kinase Cα 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 DD.
- renin-angiotensin-aldosterone system (RAAS)
- diastolic dysfunction
- passive stiffness
- titin phosphorylation
- Copyright © 2015, American Journal of Physiology - Heart and Circulatory Physiology