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

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.

Decreased Expression of Canstatin in Rat Model of Monocrotaline-Induced Pulmonary Arterial Hypertension: Protective Effect of Canstatin on Right Ventricular Remodeling

“…Control rats were injected with the same volume of saline (Cont). Three weeks after monocrotaline injection, a decrease in acceleration time (AT)/ejection time (ET) ratio and increase in lung weight (LW) and RV weight (RVW), commonly observed features in a rat model of monocrotaline-induced PAH [ 10 , 11 ], were confirmed ( Table 1 ). The plasma concentration of canstatin in PAH rats (2 weeks: 24.4 ± 4.5 ng/mL, 3 weeks 45.3 ± 1.7 ng/mL) was significantly decreased compared with Cont (2 weeks: 54.7 ± 8.2 ng/mL, 3 weeks: 66.4 ± 4.9 ng/mL) ( p < 0.01, Figure 1 A,B).…”

“…RV fibrosis is observed in a rat model of monocrotaline-induced PAH [ 11 ]. Thus, we examined the effects of canstatin on RV fibrosis by picrosirius red staining.…”

Fuzi and Banxia Combination, Eighteen Antagonisms in Chinese Medicine, Aggravates Adriamycin‐Induced Cardiomyopathy Associated with PKA/β2AR‐Gs Signaling

“…For the assessment of histopathological changes, heart tissues fixed with 4% buffered paraformaldehyde were embedded in paraffin, and 3-5 μ m thick sections were prepared. Sections were then stained with hematoxylin and eosin or Masson trichrome staining as previously described [ 15 ].…”

“…Apoptotic nuclei were detected by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) as previously described [ 15 ]. Briefly, paraffin sections of heart tissue were routinely dewaxed, rehydrated, and treated with 3% H 2 O 2 buffer blocked with endogenous peroxidase followed by 30 min proteolytic digestion in proteinase K (20 μ g/ml in 10 mM Tris/HCl, pH 7.4) at 37°C.…”

“…Physiologically, the inotropic response to catecholamine stimulation is mediated mainly by β 1AR, while the β 2AR-Gs-mediated cAMP response is suppressed by the coactivated β 2AR-Gi signaling [ 14 ]. Pathologically, in contrast to the predominant role of β 1AR in heart failure (HF), the balance between toxic versus protective effects for β 2AR in HF has received great attention [ 15 ]. Our previous study revealed that alcohol amine alkaloids of Fuzi exhibited β 2AR stimulating effect by increasing cAMP levels in HEK 293T cells [ 16 ].…”