Open Access

Stage‑dependent changes of β2‑adrenergic receptor signaling in right ventricular remodeling in monocrotaline‑induced pulmonary arterial hypertension

  • Authors:
    • Fengjiao Sun
    • Zhiqiang Lu
    • Yidan Zhang
    • Shihan Geng
    • Mengxi Xu
    • Liman Xu
    • Yingying Huang
    • Pengwei Zhuang
    • Yanjun Zhang
  • View Affiliations

  • Published online on: February 1, 2018     https://doi.org/10.3892/ijmm.2018.3449
  • Pages: 2493-2504
  • Copyright: © Sun et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

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.
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May-2018
Volume 41 Issue 5

Print ISSN: 1107-3756
Online ISSN:1791-244X

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Spandidos Publications style
Sun F, Lu Z, Zhang Y, Geng S, Xu M, Xu L, Huang Y, Zhuang P and Zhang Y: Stage‑dependent changes of β2‑adrenergic receptor signaling in right ventricular remodeling in monocrotaline‑induced pulmonary arterial hypertension. Int J Mol Med 41: 2493-2504, 2018
APA
Sun, F., Lu, Z., Zhang, Y., Geng, S., Xu, M., Xu, L. ... Zhang, Y. (2018). Stage‑dependent changes of β2‑adrenergic receptor signaling in right ventricular remodeling in monocrotaline‑induced pulmonary arterial hypertension. International Journal of Molecular Medicine, 41, 2493-2504. https://doi.org/10.3892/ijmm.2018.3449
MLA
Sun, F., Lu, Z., Zhang, Y., Geng, S., Xu, M., Xu, L., Huang, Y., Zhuang, P., Zhang, Y."Stage‑dependent changes of β2‑adrenergic receptor signaling in right ventricular remodeling in monocrotaline‑induced pulmonary arterial hypertension". International Journal of Molecular Medicine 41.5 (2018): 2493-2504.
Chicago
Sun, F., Lu, Z., Zhang, Y., Geng, S., Xu, M., Xu, L., Huang, Y., Zhuang, P., Zhang, Y."Stage‑dependent changes of β2‑adrenergic receptor signaling in right ventricular remodeling in monocrotaline‑induced pulmonary arterial hypertension". International Journal of Molecular Medicine 41, no. 5 (2018): 2493-2504. https://doi.org/10.3892/ijmm.2018.3449