Abstract
BackgroundIncreased Rho‐kinase activity in circulating leucocytes is observed in heart failure with reduced ejection fraction (HFrEF). However, there is little information in HFrEF regarding other Rho‐kinase pathway components an on the relationship between Rho‐kinase and apoptosis. Here, Rho‐kinase activation levels and phosphorylation of major downstream molecules and apoptosis levels were measured for the first time both in HFrEF patients and healthy individuals.MethodsCross‐sectional study comparing HFrEF patients (n = 20) and healthy controls (n = 19). Rho‐kinase activity in circulating leucocytes (peripheral blood mononuclear cells, PBMCs) was determined by myosin light chain phosphatase 1 (MYPT1) and ezrin‐radixin‐moesin (ERM) phosphorylation. Rho‐kinase cascade proteins phosphorylation p38‐MAPK, myosin light chain‐2, JAK and JNK were also analysed along with apoptosis.ResultsMYPT1 and ERM phosphorylation were significantly elevated in HFrEF patients, (3.9‐ and 4.8‐fold higher than in controls, respectively). JAK phosphorylation was significantly increased by 300% over controls. Phosphorylation of downstream molecules p38‐MAPK and myosin light chain‐2 was significantly higher by 360% and 490%, respectively, while JNK phosphorylation was reduced by 60%. Catecholamine and angiotensin II levels were significantly higher in HFrEF patients, while angiotensin‐(1‐9) levels were lower. Apoptosis in circulating leucocytes was significantly increased in HFrEF patients by 2.8‐fold compared with controls and significantly correlated with Rho‐kinase activation.ConclusionRho‐kinase pathway is activated in PMBCs from HFrEF patients despite optimal treatment, and it is closely associated with neurohormonal activation and with apoptosis. ROCK cascade inhibition might induce clinical benefits in HFrEF patients, and its assessment in PMBCs could be useful to evaluate reverse remodelling and disease regression.
Highlights
Increased neurohormonal drive in heart failure (HF), mainly as a result of sympathetic and renin-angiotensin system (RAS) activation, significantly contributes to pathological cardiac remodelling and disease progression.[1,2] Both neurohormonal systems promote activation of the small protein RhoA signalling pathway and its target Rho-kinase (ROCK)
In normotensive Brown Norway rats (BN), an preclinical model with genetically determined high angiotensin-converting enzyme (ACE) and angiotensin II levels,[15,16] and we previously found significantly increased phosphorylation of myosin light chain phosphatase 1 (MYPT1), ERM and p38-Mitogen-activated protein kinases (MAPKs) as well as increased levels of p65-NF-κB at the same time in the left ventricle (LV) and in peripheral blood mononuclear cells (PBMCs), and fasudil reduced them to levels observed in their respective controls.[17]
This study examined levels of key RhoA/ROCK pro-remodelling signalling pathway molecules in PMBCs from heart failure and reduced ejection fraction (HFrEF) patients
Summary
Increased neurohormonal drive in heart failure (HF), mainly as a result of sympathetic and renin-angiotensin system (RAS) activation, significantly contributes to pathological cardiac remodelling and disease progression.[1,2] Both neurohormonal systems promote activation of the small protein RhoA signalling pathway and its target Rho-kinase (ROCK). In order to assess more comprehensively the pathophysiological role of the ROCK cascade activation in PBMCs in human HFrEF, the purpose of the study was to relate Rho-kinase activation levels with the main ROCK downstream molecules associated with myocardial remodelling as well as to apoptosis levels in circulating leucocytes in patients with HFrEF. The direct relationship of ROCK activation in the myocardium and in PBMCs was further examined in a preclinical model with activation of the renin-angiotensin system and high cardiovascular ROCK levels.[17]
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