5-HT2B Receptor Antagonists Inhibit Fibrosis and Protect from RV Heart Failure

Abstract

Objective. The serotonin (5-HT) pathway was shown to play a role in pulmonary hypertension (PH), but its functions in right ventricular failure (RVF) remain poorly understood. The aim of the current study was to investigate the effects of Terguride (5-HT2A and 2B receptor antagonist) or SB204741 (5-HT2B receptor antagonist) on right heart function and structure upon pulmonary artery banding (PAB) in mice. Methods. Seven days after PAB, mice were treated for 14 days with Terguride (0.2 mg/kg bid) or SB204741 (5 mg/kg day). Right heart function and remodeling were assessed by right heart catheterization, magnetic resonance imaging (MRI), and histomorphometric methods. Total secreted collagen content was determined in mouse cardiac fibroblasts isolated from RV tissues. Results. Chronic treatment with Terguride or SB204741 reduced right ventricular fibrosis and showed improved heart function in mice after PAB. Moreover, 5-HT2B receptor antagonists diminished TGF-beta1 induced collagen synthesis of RV cardiac fibroblasts in vitro. Conclusion. 5-HT2B receptor antagonists reduce collagen deposition, thereby inhibiting right ventricular fibrosis. Chronic treatment prevented the development and progression of pressure overload-induced RVF in mice. Thus, 5-HT2B receptor antagonists represent a valuable novel therapeutic approach for RVF.

Maintained right ventricular pressure overload induces ventricular–arterial decoupling in mice

“…However, in accordance with the previously published experimental studies (Egemnazarov et al, 2015;Kapur et al, 2013;Janssen et al, 2015), we herein demonstrate that chronic pressure overload resulted in RV hypertrophy, dilatation, impaired systolic as well as diastolic function and increased RV contractility accompanied by ventricular-arterial decoupling.…”

“…Pulmonary artery banding (PAB) was performed as described previously by our group (Novoyatleva et al, 2013;Kojonazarov et al, 2013;Janssen et al, 2015).…”

Structure-Based Scaffold Repurposing for G Protein-Coupled Receptors: Transformation of Adenosine Derivatives into 5HT2B/5HT2C Serotonin Receptor Antagonists

“…14,40 Their experimental use in liver protection has been demonstrated; 5HT 2B R blockade reduces chronic fibrosis and enhances hepatic regeneration. 14 A 3 AR is highly expressed in the liver, and its agonists are also of interest for the treatment of liver disease. 20 Thus, a combined agent with both 5HT 2B R antagonist and A 3 AR agonist activity might have a synergistic benefit in the liver.…”

“…13 In mouse models of coronary function, 5HT 2B R antagonists reduced collagen deposits and the resultant right ventricular fibrosis (RVF). 14 A 5HT 2B R antagonist is also under development for irritable bowel syndrome. 18 Therefore, the goal of this study is to discover selective 5HT 2B R antagonists that might have in vivo activities indicative of the potential for disease treatment.…”

Inhibition of 5‐Hydroxytryptamine Receptor 2B Reduced Vascular Restenosis and Mitigated the β‐Arrestin2–Mammalian Target of Rapamycin/p70S6K Pathway

“…The vascular effects of 5‐HT are mediated primarily by 5‐HT1 and 5‐HT2 receptors, which belong to the G‐protein–coupled receptor family 3. 5‐HT receptor 2B (5‐HT2BR) has a key role in the previously mentioned 5‐HT–related diseases, including cardiac hypertrophy, valve hyperplasia, and fibrosis 19, 20, 21. 5‐HT2BR induced hypersensitivity of arteries to 5‐HT in hypertension and PAH22, 23, 24, 25, 26, 27 and was required for vascular remodeling in PAH 22…”