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

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 factorα (VEGF) protein expressions and elevated serum levels of interleukin 6 (IL-6) and tumour necrotic factor α (TNFα) 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.

Interleukin-6 and pulmonary hypertension: from physiopathology to therapy

“…Resveratrol (trans-3, 5, 4’-trihydroxystilbene) can inhibit IL-6 expression and PH vascular remodeling by inhibiting multiple signaling pathways, such as ERK/MAPK, NF-κB, bone morphogenetic protein (BMP), PI3K/AKT, and hypoxia inducible factor-1α (HIF-1α) ( 32 ). The metabotropic glutamate receptor 5 (mGluR5) inhibitor 3-((2-methyl-4-thiazolyl) ethynyl) pyridine (MTEP) inhibits the signaling cascade involving PI3K/AKT, p38/MAPK, angiopoietin 2 and VEGF ( 56 ). Baicalin reduces chronic hypoxia-induced PH by downregulating the p38/MAPK/MMP-9 pathway ( 121 ).…”

“…Sodium tanshinone II sulfonate A (STS) alleviates hypoxia-induced PH by promoting apoptosis, inhibiting the PI3K/AKT/mTOR pathway, upregulating autophagy, and inhibiting inflammatory responses ( 62 ). Resveratrol and 3-((2-methyl-4-thiazolyl)ethynyl)pyridine inhibit multiple signaling pathways, including the PI3K/AKT pathway, to treat PH ( 32 , 56 ). Luteolin inhibits PI3K/AKT by downregulating the expression of LATS1, YAP and PDGF-B and is therapeutic for experimental PH ( 40 ).…”