Researchers discovered that the blockade of metabotropic glutamate receptor 5 (mGluR5) attenuates the pathological remodeling of the heart in pulmonary arterial hypertension (PAH), as published in Clinical and Experimental Pharmacology and Physiology.

The mGluR5 is broadly expressed in the heart and mediates the activation of the PI3K/AKT and P38MAPK signaling cascades. This then increases cell survival proliferation, which then drives the pulmonary and cardiac remodeling typically observed in PAH.

“We hypothesized that mGluR5 is involved in the pathogenesis of PAH; as such, a blockade of its signaling may yield beneficial effects in PAH,” Mprah and colleagues wrote.


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They thus decided to investigate the role of mGluR5 in pathological cardiac remodeling by conducting experiments of monocrotaline (MCT)-induced PAH rats. 

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They discovered that mGluR5 is upregulated in the right ventricle of MCT-induced PAH rats, offering the first clue that it may play a significant role in PAH pathogenesis. In addition, they discovered that the blockade of mGluR5 in MCT-induced PAH rats led to:

  • The preservation of cardiac function
  • A reduction in right ventricular hypertrophy and collagen expression
  • A decrease in protein expressions of angiopoietin 2 and vascular endothelial growth factor
  • A decrease in protein expressions of PI3K, AKT, and P38MAPK
  • The attenuation of PAH-induced inflammation

In summary, the researchers made 2 important discoveries: mGluR5 is upregulated in PAH rat models and that its blockade improved the clinical picture in PAH rat models. This is significant because PAH treatment currently is limited; the life expectancy of patients with PAH is comparable to that of metastatic cancer patients, they said.

“Our experiment demonstrated that blockade of mGluR5 using [methyl-thiazolyl ethynyl pyridine] is an effective regimen to ameliorate several pathological outcomes in MCT-induced PAH, including increases in [right ventricular systolic pressure], contractile dysfunctions, right ventricular and cardiac hypertrophy, inflammation, and fibrosis,” the researchers concluded.

Reference

Mprah R, Ma Y, Adzika GK, et al. Metabotropic glutamate receptor 5 blockade attenuates pathological cardiac remodeling in pulmonary arterial hypertension. Clin Exp Pharmacol Physiol. Published online February 8, 2022. doi:10.1111/1440-1681.13633