Activation of bone morphogenetic protein type 1A receptors (BMPR1A) by THR184 halts the progression of the left ventricular remodelling under pressure overload
Authors: Salido Medina AB , Hurle MA , Nistal JF , Garcia R 
Published: June 2022

Abstract

Funding Acknowledgements
Type of funding sources: Public grant(s) – National budget only. Main funding source(s): This work was supported by grants from Spain´s Ministerio de Economía y Competitividad [(PI18/00543, CIBERCV (CB16/11/00264), co-funded by Fondo Europeo de Desarrollo Regional (FEDER)]; Instituto de Investigación Sanitaria Marqués de Valdecilla, IDIVAL (INNVAL18/20; PREVAL18/03); Grants4Targets from BAYER AG (ID 2017-03-2088).

Background
Aortic valve stenosis (AS) confronts the left ventricle (LV) with a progressive pressure overload that leads to myocardial remodelling (hypertrophy and fibrosis) and ultimately to heart failure. BMP7, through BMPR1A-mediated pSMAD1/5/(8)9 signalling, protects the LV against maladaptive remodelling. Small BMP-based molecules for therapeutic applications are gaining momentum in different clinical fields. A synthetic peptide agonist of BMPR1A, THR184, has been reported to prevent and reverse experimental renal fibrotic processes.

Purpose
To assess the potential of THR184 to halt or reverse the LV pathological remodelling induced by pressure overload in mice and evaluate the mechanisms involved in cultured cells.

Methods and Results
Mice subjected to a 4-week transverse aortic constriction (TAC) period received daily i.p injections of THR184 (n=9) (5µg/g) or saline (n=10) during the 3rd and 4th weeks after TAC, when LV remodelling was already ongoing. LV morphology and function were assessed by echocardiography. LV samples were analysed by qPCR and Western blot. THR184 halted the LV morpho-functional deterioration developed four weeks after TAC as compared to the saline group: [LV mass: THR184, 3.74±0.27 mg vs saline, 4.44±0.71 mg*; long-axis systolic function (MAPSE): THR184, 0.60±0.04 mm vs saline, 0.49±0.06 mm*; LV filling pressures (E/e’): THR184, 36.92±5.41 vs saline, 58.41±19.34**]. Moreover, THR184 partially reverted LV dysfunction, both systolic (MAPSE: 4 wk, 0.60±0.04 mm vs 2 wk, 0.49±0.03 mm***) and diastolic (E/e’: 4 wk, 36.92±5.41 vs 2 wk, 46.87±10.04*). The myocardial overexpression of the remodelling-related genes induced by TAC was attenuated by THR184 compared to saline: [Collagen I (Col I): THR184, 6.77±1.72 vs saline, 14.61±1.94 ***); β myosin heavy chain (β-MHC): THR184, 3.08±1.52 vs saline, 5.67±1.14*]. The expression of pSMAD1/5/(8)9 was reduced in saline-treated TAC mice (TAC, 0.67±0.09 vs sham, 1.04±0.05*), while it was rescued in THR184-treated TAC mice (THR184, 1.11±0.14 vs saline, 0.67±0.09**). In cultured cells, THR184 reduced TGF-β1-mediated transcriptional activation of Col I in 3T3 fibroblasts (THR184, 2.40±0.45 vs TGF-β1, 4.34±0.55***) and β-MHC in H9C2 cardiomyocytes (THR184, 1.02±0.38 vs TGF-β1, 4.10±1.56*). The involvement of BMPR1A in the effects of THR184 was supported by the antagonism with LDN or DMH2.

Conclusion
THR184 activated BMPR1A signalling through pSMAD1/5/(8)9 to halt the maladaptive remodelling of the LV by counteracting TGF-β1-mediated pro-fibrotic and pro-hypertrophic actions. We provide a preclinical proof-of-concept on THR184, a BMP7-based BMPR1A agonist, to treat the deleterious consequences of LV pressure overload.