Metabotropic glutamate receptor 5 blockade attenuates pathological cardiac remodelling in pulmonary arterial hypertension

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Abstract
Pulmonary arterial hypertension (PAH) is characterized by cardiac remodelling. Glutaminolysis plays a crucial role in PAH‐induced remodelling. The metabotropic glutamate receptor 5 (mGluR5) may mediate this process. This study investigated whether or not the blockade of mGluR5 may attenuate PAH‐induced pathological cardiac remodelling. Pulmonary arterial hypertension was induced by intraperitoneally injecting male Sprague‐Dawley (SD) rats with 60 mg/kg of monocrotaline (MCT). 3‐((2‐Methyl‐4‐thiazolyl)ethynyl)pyridine (MTEP) (10 mg/kg intraperitoneally) was used as a therapeutic intervention to block mGluR5. Cardiac functions were assessed with right heart catheterization and electrocardiography. Alterations in protein expressions and inflammatory markers were investigated using western blot and enzyme‐linked immunosorbent assay (ELISA), respectively. Increased right ventricular systolic pressure (RSVP), elevated protein expressions of mGluR5, collagen types I and III and cartilage intermediate layer protein 1 (CILP1), enhanced phosphorylation of phosphatidylinositol 3‐kinase (PI3K), AKT and p38 mitogen‐activated protein kinase (P38MAPK), increased angiopoietin 2 (Ang 2) and vascular endothelial growth factor‐α (VEGF) protein expressions and elevated serum levels of interleukin 6 (IL‐6) and tumour necrotic factor α (TNF‐α) were observed in MCT‐induced PAH rats. MTEP improved hemodynamics and right ventricular hypertrophy. MTEP also attenuated MCT‐induced elevations in the protein expressions of mGluR5, collagen types I and III, CILP1, Ang 2 and VEGF and decreased PI3K, AKT and P38MAPK phosphorylations and inflammatory cytokine levels. Metabotropic glutamate receptor 5 blockade using MTEP ameliorates PAH‐induced pathological right cardiac remodelling via inhibiting the signalling cascade involving PI3K/AKT, P38MAPK, Ang 2 and VEGF.

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