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

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 β(2)-adrenergic receptor (β(2)-AR) signaling has been reported to induce myocardiotoxicity in patients with left heart failure. However, the role of β(2)-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 β(2)-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 β(2)-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 β(2)-AR-G(s)-protein kinase A/Ca(2+)/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 β(2)-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.