Department of Medical Sciences, iBiMED-Institute of Biomedicine, University of Aveiro, Aveiro, Portugal.
Department of Surgery and Physiology, UnIC-Cardiovascular Research and Development Centre, Faculty of Medicine, University of Porto, Porto, Portugal.
PLoS One. 2020 Sep 18;15(9):e0237000. doi: 10.1371/journal.pone.0237000. eCollection 2020.
Currently, aortic valve replacement is the only treatment capable of relieving left ventricle pressure overload in patients with severe aortic stenosis. It aims to improve cardiac function and revert hypertrophy, by triggering myocardial reverse remodeling. Despite immediately relieving afterload, reverse remodeling turns out to be extremely variable. Among other factors, the extent of reverse remodeling may depend on how well ubiquitin-proteasome system tackle hypertrophy. Therefore, we assessed tagged ubiquitin and ubiquitin ligases in the left ventricle collected from patients undergoing valve replacement and tested their association to the degree of reverse remodeling. Patients were classified according to the regression of left ventricle mass (ΔLVM) and assigned to complete (ΔLVM≥15%) or incomplete (ΔLVM≤5%) reverse remodeling groups. No direct inter-group differences were observed. Nevertheless, correlation analysis supports a fundamental role of the ubiquitin-proteasome system during reverse remodeling. Indeed, total protein ubiquitination was associated to hypertrophic indexes such as interventricular septal thickness (r = 0.55, p = 0.03) and posterior wall thickness (r = 0.65, p = 0.009). No significant correlations were observed for Muscle Ring Finger 3. Surprisingly, though, higher levels of atrogin-1 were associated to postoperative interventricular septal thickness (r = 0.71, p = 0.005). In turn, Muscle Ring Finger 1 correlated negatively with this postoperative hypertrophy marker (r = -0.68, p = 0.005), suggesting a cardioprotective role during reverse remodeling. No significant correlations were found with left ventricle mass regression, although a trend for a negative association between the ligase Murine Double Minute 2 and mass regression (r = -0.44, p = 0.10) was found. Animal studies will be necessary to understand whether this ligase is protective or detrimental. Herein, we show, for the first time, an association between the preoperative myocardial levels of ubiquitin ligases and postoperative hypertrophy, highlighting the therapeutic potential of targeting ubiquitin ligases in incomplete reverse remodeling.
目前，主动脉瓣置换术是唯一能够缓解严重主动脉瓣狭窄患者左心室压力超负荷的治疗方法。它旨在通过触发心肌逆重构来改善心功能并逆转肥厚。尽管术后立即减轻了后负荷，但逆重构的结果却极为多变。除其他因素外，逆重构的程度可能取决于泛素-蛋白酶体系统对肥厚的处理程度。因此，我们评估了接受瓣膜置换术的患者左心室中标记的泛素和泛素连接酶，并测试了它们与逆重构程度的相关性。根据左心室质量（ΔLVM）的回归将患者分类，并将其分为完全（ΔLVM≥15%）或不完全（ΔLVM≤5%）逆重构组。未观察到两组间的直接差异。然而，相关性分析支持泛素-蛋白酶体系统在逆重构过程中的基本作用。事实上，总蛋白泛素化与室间隔厚度（r = 0.55，p = 0.03）和后壁厚度（r = 0.65，p = 0.009）等肥厚指标相关。Muscle Ring Finger 3 则无显著相关性。不过，令人惊讶的是，Atrogin-1 的水平与术后室间隔厚度相关（r = 0.71，p = 0.005）。相反，Muscle Ring Finger 1 与该术后肥厚标志物呈负相关（r = -0.68，p = 0.005），提示在逆重构过程中有心脏保护作用。尽管与左心室质量回归呈负相关（r = -0.44，p = 0.10），但与 ligase Murine Double Minute 2 之间存在负相关趋势，但未发现与左心室质量回归有显著相关性。需要进行动物研究以了解该连接酶是保护还是有害。在此，我们首次显示术前心肌泛素连接酶水平与术后肥厚之间存在相关性，强调了针对不完全逆重构的泛素连接酶的治疗潜力。
