Glutaminolysis: A Driver of Vascular and Cardiac Remodeling in Pulmonary Arterial Hypertension

Abstract

Pulmonary arterial hypertension (PAH) is a decimating ailment described by chronic precapillary pulmonary hypertension, an elevated mean pulmonary arterial pressure with a normal pulmonary capillary wedge pressure, and a raised pulmonary vascular resistance resulting in increased right ventricular afterload culminating in heart failure and death. Current PAH treatments regulate the vasodilatory/vasoconstrictory balance of pulmonary vessels. However, these treatment options are unable to stop the progression of, or reverse, an already established disease. Recent studies have advanced a metabolic dysregulation, featuring increased glutamine metabolism, as a mechanism driving PAH progression. Metabolic dysregulation in PAH leads to increased glutaminolysis to produce substrate to meet the high-energy requirement by hyperproliferative and apoptosis-resistant pulmonary vascular cells. This article explores the role of glutamate metabolism in PAH and how it could be targeted as an anti-remodeling therapeutic strategy.

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

“…This study builds on an earlier report that mGluR5 is abundantly expressed in the RV 34 by examining its functional role in the heart in the setting of PAH. PI3K/AKT and P38MAPK signalling result in increased cell survival, hyperproliferation, myocyte hypertrophy, excessive inflammatory responses and fibrosis, which characterize remodelling in PAH 10,35 (Figure 7). AKT is a primary mediator of the PI3K signalling cascade 36 .…”

“…Pulmonary arterial hypertension‐induced cardiac remodelling involves changes in organ‐level hemodynamics to tissue stiffening, altered myocyte contractility and dysregulations in energetics 6–9 . Pulmonary arterial hypertension‐associated dysregulations in energetics (metabolic dysregulation) involving the anaplerotic use of glutamate (in glutaminolysis) drive PAH‐induced maladaptive cardiac remodelling 10 . Admittedly, increased glutaminolysis has been reported in the RV of PAH rat models and human PAH patients 11 .…”

“…Admittedly, increased glutaminolysis has been reported in the RV of PAH rat models and human PAH patients 11 . The increased glutaminolysis in the RV in PAH may trigger the upregulation of glutamate receptors 10 …”

“…Metabotropic glutamate receptor 5 mediates the activation of PI3K/AKT 15,16 and p38 mitogen‐activated protein kinase (P38MAPK) 17,18 signalling cascades. The activation of PI3K/AKT and P38MAPK signalling axes increases cell survival and proliferation, driving PAH‐associated remodelling 10,19 . Prolonged PI3K/AKT activation promotes pathological hypertrophy 20,21 .…”

Mitochondrial Metabolism, Redox, and Calcium Homeostasis in Pulmonary Arterial Hypertension

“…A global cellular metabolomics overview suggests that a set of altered mitochondrial metabolites contributes to the pathogenesis of PH [ 40 , 41 ]. Studies have revealed that cells of the pulmonary vasculature have a strong dependence on glutamine, which leads to excessive proliferation [ 42 ]. In cells, glutamine is the critical amino acid in several biochemical reactions, and is required for glutamate synthesis by glutaminolysis.…”