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

Abstract

Pulmonary arterial hypertension (PAH) is a progressive disease characterized by elevated pulmonary arterial pressure due to increased pulmonary vascular resistance, secondary to sustained pulmonary vasoconstriction and excessive obliterative pulmonary vascular remodeling. Work over the last decade has led to the identification of a critical role for metabolic reprogramming in the PAH pathogenesis. It is becoming clear that in addition to its role in ATP generation, the mitochondrion is an important organelle that regulates complex and integrative metabolic- and signal transduction pathways. This review focuses on mitochondrial metabolism alterations that occur in deranged pulmonary vessels and the right ventricle, including abnormalities in glycolysis and glucose oxidation, fatty acid oxidation, glutaminolysis, redox homeostasis, as well as iron and calcium metabolism. Further understanding of these mitochondrial metabolic mechanisms could provide viable therapeutic approaches for PAH patients.

Estimation of Serum Calcium Level in the Patients of Hypertension

“…Calcium also contributed in development of essential hypertension because proper concentration of calcium regulates the smooth muscular tone of vessels and peripheral resistance. 18 Some researchers suggested that any change in intracellular calcium level can disturbed the secretion and action of different hormones like catecholamine which can lead in pathogenesis of Hypertension. 19 Intracellular calcium also regulates the renin-angiotensin system, which maintains normal blood pressure, vascular tone, and peripheral resistance.…”

Inactivating the Uninhibited: The Tale of Activins and Inhibins in Pulmonary Arterial Hypertension

“…A small number of SMCs with high Notch3 expression penetrated the internal elastic lamina, resulting in neointimal lesions, severely narrowing the vessel lumen in a house dust mite PAH mice model [ 18 ]. Mitochondrial dysfunctions in ECs and SMCs have been implicated as a cause of the metabolic phenotype that is increasingly observed in PAH patients with different etiologies [ 27 ]. The metabolic dysregulation caused by mitochondrial dysfunction in the vasculature includes aerobic glycolysis (also known as the Warburg Effect), decreased fatty acid oxidation, insulin resistance, and alterations in the lipid profile of patients [ 28 ].…”

Mitochondrial dysfunction in pulmonary arterial hypertension

“…Antioxidants are another potential therapeutic approach targeting the disruption of redox homeostasis in PAH patients. Antioxidant system agonists, inhibitors of ROS production, and modulators of ROS-induced toxicity can reverse pulmonary artery remodeling and improve right heart function in animal models of PAH, such as sod-mimicking metalloporphyrin manganese (III) tetrakis (4-benzoate acid) porphyrin phenoline (MnTBAP), SOD-mimicking drug TEMPOL, MAOA inhibitor Clorgyline, GKT137831 inhibitor NOX4, etc., ( Bertero et al, 2016 ; Dumas et al, 2018 ; Ge et al, 2018 ; Liang et al, 2022 ). Coenzyme Q (CoQ), an essential substance for mitochondrial and antioxidant responses, can also improve cardiac function in patients with PAH by improving mitochondrial and redox metabolism ( Egnatchik et al, 2017 ).…”

“…Similar to atherosclerosis, the early pathological lesions of PAH are manifested by endothelial dysfunction and apoptosis, and the late stage manifests as hyperproliferative and anti-apoptotic endothelial and smooth muscle cells to remodel pulmonary blood vessels, which in turn increases pulmonary artery pressure and results in right ventricular dysfunction and failure ( Michelakis, 2006 ; Xu et al, 2007 ; Tuder et al, 2013 ; Thompson and Lawrie, 2017 ; Thenappan et al, 2018 ). Mechanistically, the mechanism of pulmonary vasoconstriction and remodeling is very complex, including abnormal activation of growth factor signaling pathway ( Dumas et al, 2018 ; Ma et al, 2019 ), abnormal ion channel function ( Lambert et al, 2019 ), inflammatory injury ( Siques et al, 2021 ), oxidative stress ( Siques et al, 2021 ), abnormal energy metabolism ( Harvey and Chan, 2017 ), oxygen glycolysis ( Liang et al, 2022 ), fatty acid oxidation ( Harvey and Chan, 2017 ), etc. Mitochondria are recognized sensors of oxygen and fuel, and the most important energy-producing site of the body ( Dromparis and Michelakis, 2013 ).…”