Stage‑dependent changes of β2‑adrenergic receptor signaling in right ventricular remodeling in monocrotaline‑induced pulmonary arterial hypertension.
Stage‑dependent changes of β2‑adrenergic receptor signaling in right ventricular remodeling in monocrotaline‑induced pulmonary arterial hypertension.
复制标题
野百合碱诱导的肺动脉高压右心室重构中 2-肾上腺素受体信号的阶段依赖性变化
DOI：
10.3892/ijmm.2018.3449
复制
发表时间：
2018-05
影响因子：
5.4
通讯作者：
Zhang Y
中科院分区：
文献类型：
--
作者：
Sun F;Lu Z;Zhang Y;Geng S;Xu M;Xu L;Huang Y;Zhuang P;Zhang Y
右心室（RV）重塑加上广泛的细胞凋亡，以响应无限制的生物力学应力可能会导致RV衰竭（RVF），这是大多数肺动脉高压（PAH）患者死亡的直接原因。β2-肾上腺素能受体（β2-AR）信号的过度表达已被报道可诱导左心衰患者的心肌毒性。然而，β2-AR信号在PAH发展的病理生理学中的作用仍然是难以捉摸的。为了解决这个问题，本研究调查了在RVF中给予野百合碱（MCT; 60 mg/kg，i. p.）后心肺功能和结构的变化，以及纤维化和凋亡调节因子的表达。在大鼠中诱导PAH。在6周的时间内记录心脏功能和结构，重塑和凋亡，以及G蛋白偶联受体（GPCR）和β2-AR信号。在早期阶段，在MCT诱导的PAH动物中观察到肺动脉压升高、肺部病变、RV肥大、左心室（LV）功能亢进证据和心率加快。右心血管紧张素Ⅱ受体1b型（Agtr 1b）、Agtr 2和Agt水平显著上调，β2-AR磷酸化Ser（355，356）表达持续下降。随着疾病进展，观察到LV功能障碍，表现为LV收缩压降低和LV舒张末期压升高，伴有循环脑钠肽水平持续升高。值得注意的是，尽管RV收缩力增强，但观察到心肌细胞凋亡水平增加和伴随的RV重塑，包括肥大、扩张、炎症和纤维化。此外，在PAH晚期观察到GPCR信号的改变和β2-AR-Gs-蛋白激酶A/Ca 2 +/钙调蛋白依赖性激酶II信号的激活。这些结果表明，在PAH进展过程中，MCT治疗导致适应性和适应不良的RV重构和凋亡，这伴随着β2-AR信号的明显变化。因此，这些结果使研究人员能够更好地了解MCT诱导的PAH的病理生理学，以及确定新疗法的效果。
Right ventricular (RV) remodeling coupled with extensive apoptosis in response to unrestrained biomechanical stress may lead to RV failure (RVF), which is the immediate cause of death in the majority of patients with pulmonary arterial hypertension (PAH). Overexpression of β2-adrenergic receptor (β2-AR) signaling has been reported to induce myocardiotoxicity in patients with left heart failure. However, the role of β2-AR signaling in the pathophysiology of PAH development has remained elusive. To address this issue, the present study investigated the changes in cardiopulmonary function and structure, as well as the expression of regulators of fibrosis and apoptosis in RVF following monocrotaline (MCT; 60 mg/kg, i.p.)-induced PAH in rats. Cardiopulmonary function and structure, remodeling and apoptosis, as well as G protein-coupled receptor (GPCR) and β2-AR signaling, were documented over a period of 6 weeks. In the early stages, elevated pulmonary arterial pressure, pulmonary lesions, RV hypertrophy, evidence of left ventricular (LV) hyperfunction and accelerated heart rate were observed in animals with MCT-induced PAH. The levels of angiotensin II receptor type 1b (Agtr1b), Agtr2 and Agt were markedly upregulated and the expression of β2-AR phospho-Ser(355,356) steadily decreased in the right heart. As the disease progressed, LV dysfunction was observed, as evidenced by decreased LV systolic pressure and increased LV end-diastolic pressure, which was accompanied by a sustained increase in circulating brain natriuretic peptide levels. Of note, increased levels of cardiomyocyte apoptosis and concomitant RV remodeling, including hypertrophy, dilatation, inflammation and fibrosis, were observed, despite the enhanced RV contractility. Furthermore, alterations in GPCR signaling and activation in β2-AR-Gs-protein kinase A/Ca2+/calmodulin-dependent kinase II signaling were observed in the late stages of PAH. These results suggested that treatment with MCT results in adaptive and maladaptive RV remodeling and apoptosis during the progression of PAH, which is accompanied by distinct changes in the β2-AR signaling. Therefore, these results enable researchers to better understand of pathophysiology of MCT-induced PAH, as well as to determine the effects of novel therapies.
登录
查看更多内容
影响因子：
14.9
作者：
Chen C;Ridzon DA;Broomer AJ;Zhou Z;Lee DH;Nguyen JT;Barbisin M;Xu NL;Mahuvakar VR;Andersen MR;Lao KQ;Livak KJ;Guegler KJ
通讯作者：
Guegler KJ
影响因子：
5.3
作者：
Grailer JJ;Haggadone MD;Sarma JV;Zetoune FS;Ward PA
通讯作者：
Ward PA
影响因子：
4.6
作者：
Ameri, Pietro;Bertero, Edoardo;Balbi, Manrico
通讯作者：
Balbi, Manrico
DOI：
10.1152/ajpheart.00369.2006
发表时间：
2006-11-01
影响因子：
4.8
作者：
Hessel, Marleen H. M.;Steendijk, Paul;van der Laarse, Arnoud
通讯作者：
van der Laarse, Arnoud
DOI：
10.1152/ajpheart.00089.2016
发表时间：
2016-07-01
影响因子：
4.8
作者：
Mendes-Ferreira, P.;Santos-Ribeiro, D.;Bras-Silva, C.
通讯作者：
Bras-Silva, C.