Mitochondrial fission produces a Warburg effect via the oxidative inhibition of prolyl hydroxylase domain-2.

Excessive mitochondrial fission and a shift to a Warburg phenotype are hallmarks of pulmonary hypertension (PH), although the mechanistic link between these processes remains unclear. We show that in pulmonary arterial endothelial cells (PAEC), Drp1 overexpression induces mitochondrial fission and increases glycolytic ATP production and glycolysis. This is due to mitochondrial reactive oxygen species (mito-ROS)-mediated activation of hypoxia-inducible factor-1α (HIF-1α) signaling, and this is linked to hydrogen peroxide (HO)-mediated inhibition of prolyl hydroxylase domain-2 (PHD2) due to its cysteine 326 oxidation and dimerization.

Chloroquine Restores eNOS Signaling in Shunt Endothelial Cells via Inhibiting eNOS Uncoupling.

Pulmonary arterial hypertension (PAH) is characterized by increased lung vascular stiffness and impaired vessel relaxation, primarily due to reduced nitric oxide (NO) production in endothelial cells. Recent studies indicate that chloroquine, an autophagy inhibitor, may help lower pulmonary arterial pressure and enhance lung vascular function. This study investigates the mechanisms underlying the chloroquine-mediated restoration of NO bioavailability in endothelial cells derived from aortopulmonary shunt lambs, a relevant model for congenital heart defect (CHD)-associated PAH.

The mitochondrial redistribution of ENOS is regulated by AKT1 and dimer status.

Previously, we have shown that endothelial nitric-oxide synthase (eNOS) dimer levels directly correlate with the interaction of eNOS with hsp90 (heat shock protein 90). Further, the disruption of eNOS dimerization correlates with its redistribution to the mitochondria. However, the causal link between these events has yet to be investigated and was the focus of this study.

Inflammatory lung injury is associated with endothelial cell mitochondrial fission and requires the nitration of RhoA and cytoskeletal remodeling.

Higher levels of extracellular nicotinamide phosphoribosyltransferase (eNAMPT), a TLR4 agonist, are associated with poor clinical outcomes in sepsis-induced acute lung injury (ALI). Little is known regarding the mechanisms by which eNAMPT is involved in ALI. Our recent work has identified a crucial role for mitochondrial dysfunction in ALI.

Prognostic nutritional index (PNI) and risk of non-alcoholic fatty liver disease and advanced liver fibrosis in US adults: Evidence from NHANES 2017-2020.

Objective: This study explored the potential association between the Prognostic Nutritional Index (PNI) and the incidence of non-alcoholic fatty liver disease (NAFLD) and advanced liver fibrosis (AF) in the adult population of the United States.

Methods: Information on 6409 participants ≥18 years old was downloaded from the U.S.

Novel Relationship between Mitofusin 2-Mediated Mitochondrial Hyperfusion, Metabolic Remodeling, and Glycolysis in Pulmonary Arterial Endothelial Cells.

The disruption of mitochondrial dynamics has been identified in cardiovascular diseases, including pulmonary hypertension (PH), ischemia-reperfusion injury, heart failure, and cardiomyopathy. Mitofusin 2 (Mfn2) is abundantly expressed in heart and pulmonary vasculature cells at the outer mitochondrial membrane to modulate fusion. Previously, we have reported reduced levels of Mfn2 and fragmented mitochondria in pulmonary arterial endothelial cells (PAECs) isolated from a sheep model of PH induced by pulmonary over-circulation and restoring Mfn2 normalized mitochondrial function.

Simvastatin restores pulmonary endothelial function in the setting of pulmonary over-circulation.

Statin therapy is a cornerstone in the treatment of systemic vascular diseases. However, statins have failed to translate as therapeutics for pulmonary vascular disease. Early pulmonary vascular disease in the setting of congenital heart disease (CHD) is characterized by endothelial dysfunction, which precedes the more advanced stages of vascular remodeling.

Mitochondrial hyperfusion induces metabolic remodeling in lung endothelial cells by modifying the activities of electron transport chain complexes I and III.

Objective: Pulmonary hypertension (PH) is a progressive disease with vascular remodeling as a critical structural alteration. We have previously shown that metabolic reprogramming is an early initiating mechanism in animal models of PH. This metabolic dysregulation has been linked to remodeling the mitochondrial network to favor fission.

Bioinformatic Analysis of Key Biomarkers and Infiltrating Immune Cells in Nonalcoholic Fatty Liver Disease.

Context: The liver is both the largest metabolic and the largest immune organ and is closely related to the mechanisms of disease development. Clarifying the immune environment of the NAFLD liver to determine its interactions with biomarkers would be beneficial in exploring the mechanisms of disease development.

Objective: The study aimed to identify biomarkers and immune cells associated with nonalcoholic fatty liver disease (NAFLD) and to analyze the correlation between key genes and immune cells in NAFLD, to improve the understanding of the mechanisms underlying NAFLD and provide potential therapeutic targets.

SOX17 Deficiency Mediates Pulmonary Hypertension: At the Crossroads of Sex, Metabolism, and Genetics.

Genetic studies suggest that SOX17 (SRY-related HMG-box 17) deficiency increases pulmonary arterial hypertension (PAH) risk. On the basis of pathological roles of estrogen and HIF2α (hypoxia-inducible factor 2α) signaling in pulmonary artery endothelial cells (PAECs), we hypothesized that SOX17 is a target of estrogen signaling that promotes mitochondrial function and attenuates PAH development via HIF2α inhibition. We used metabolic (Seahorse) and promoter luciferase assays in PAECs together with the chronic hypoxia murine model to test the hypothesis.

Nitration-mediated activation of the small GTPase RhoA stimulates cellular glycolysis through enhanced mitochondrial fission.

Mitochondrial fission and a Warburg phenotype of increased cellular glycolysis are involved in the pathogenesis of pulmonary hypertension (PH). The purpose of this study was to determine whether increases in mitochondrial fission are involved in a glycolytic switch in pulmonary arterial endothelial cells (PAECs). Mitochondrial fission is increased in PAEC isolated from a sheep model of PH induced by pulmonary overcirculation (Shunt PAEC).

The mitochondrial redistribution of eNOS is involved in lipopolysaccharide induced inflammasome activation during acute lung injury.

Acute lung injury (ALI) is a devastating clinical syndrome with no effective therapies. Inflammasome activation has been reported to play a critical role in the initiation and progression of ALI. The molecular mechanisms involved in regulating the activation of inflammasome in ALI remains unresolved, although increases in mitochondrial derived reactive oxygen species (mito-ROS) are involved.

Arginine recycling in endothelial cells is regulated BY HSP90 and the ubiquitin proteasome system.

Despite the saturating concentrations of intracellular l-arginine, nitric oxide (NO) production in endothelial cells (EC) can be stimulated by exogenous arginine. This phenomenon, termed the "arginine paradox" led to the discovery of an arginine recycling pathway in which l-citrulline is recycled to l-arginine by utilizing two important urea cycle enzymes argininosuccinate synthetase (ASS) and argininosuccinate lyase (ASL). Prior work has shown that ASL is present in a NO synthetic complex containing hsp90 and endothelial NO synthase (eNOS).

RAC1 nitration at Y IS involved in the endothelial barrier disruption associated with lipopolysaccharide-mediated acute lung injury.

Acute lung injury (ALI), a devastating illness induced by systemic inflammation e.g., sepsis or local lung inflammation e.

Activation of the mechanosensitive Ca channel TRPV4 induces endothelial barrier permeability via the disruption of mitochondrial bioenergetics.

Mechanical ventilation is a life-saving intervention in critically ill patients with respiratory failure due to acute respiratory distress syndrome (ARDS), a refractory lung disease with an unacceptable high mortality rate. Paradoxically, mechanical ventilation also creates excessive mechanical stress that directly augments lung injury, a syndrome known as ventilator-induced lung injury (VILI). The specific mechanisms involved in VILI-induced pulmonary capillary leakage, a key pathologic feature of VILI are still far from resolved.

TGF-β1 attenuates mitochondrial bioenergetics in pulmonary arterial endothelial cells via the disruption of carnitine homeostasis.

Transforming growth factor beta-1 (TGF-β1) signaling is increased and mitochondrial function is decreased in multiple models of pulmonary hypertension (PH) including lambs with increased pulmonary blood flow (PBF) and pressure (Shunt). However, the potential link between TGF-β1 and the loss of mitochondrial function has not been investigated and was the focus of our investigations. Our data indicate that exposure of pulmonary arterial endothelial cells (PAEC) to TGF-β1 disrupted mitochondrial function as determined by enhanced mitochondrial ROS generation, decreased mitochondrial membrane potential, and disrupted mitochondrial bioenergetics.

Ovine Models of Congenital Heart Disease and the Consequences of Hemodynamic Alterations for Pulmonary Artery Remodeling.

The natural history of pulmonary vascular disease associated with congenital heart disease (CHD) depends on associated hemodynamics. Patients exposed to increased pulmonary blood flow (PBF) and pulmonary arterial pressure (PAP) develop pulmonary vascular disease more commonly than patients exposed to increased PBF alone. To investigate the effects of these differing mechanical forces on physiologic and molecular responses, we developed two models of CHD using fetal surgical techniques: ) left pulmonary artery (LPA) ligation primarily resulting in increased PBF and ) aortopulmonary shunt placement resulting in increased PBF and PAP.

LPS-induced Acute Lung Injury Involves NF-κB-mediated Downregulation of SOX18.

One of the early events in the progression of LPS-mediated acute lung injury in mice is the disruption of the pulmonary endothelial barrier resulting in lung edema. However, the molecular mechanisms by which the endothelial barrier becomes compromised remain unresolved. The SRY (sex-determining region on the Y chromosome)-related high-mobility group box (Sox) group F family member, SOX18, is a barrier-protective protein through its ability to increase the expression of the tight junction protein CLDN5.

Endothelial HIF-2α contributes to severe pulmonary hypertension due to endothelial-to-mesenchymal transition.

Pulmonary vascular remodeling characterized by concentric wall thickening and intraluminal obliteration is a major contributor to the elevated pulmonary vascular resistance in patients with idiopathic pulmonary arterial hypertension (IPAH). Here we report that increased hypoxia-inducible factor 2α (HIF-2α) in lung vascular endothelial cells (LVECs) under normoxic conditions is involved in the development of pulmonary hypertension (PH) by inducing endothelial-to-mesenchymal transition (EndMT), which subsequently results in vascular remodeling and occlusive lesions. We observed significant EndMT and markedly increased expression of SNAI, an inducer of EndMT, in LVECs from patients with IPAH and animals with experimental PH compared with normal controls.

Capsaicin-induced Ca signaling is enhanced via upregulated TRPV1 channels in pulmonary artery smooth muscle cells from patients with idiopathic PAH.

Capsaicin is an active component of chili pepper and a pain relief drug. Capsaicin can activate transient receptor potential vanilloid 1 (TRPV1) channels to increase cytosolic Ca concentration ([Ca]). A rise in [Ca] in pulmonary artery smooth muscle cells (PASMCs) is an important stimulus for pulmonary vasoconstriction and vascular remodeling.

Hyper-activation of pp60 limits nitric oxide signaling by increasing asymmetric dimethylarginine levels during acute lung injury.

The molecular mechanisms by which the endothelial barrier becomes compromised during lipopolysaccharide (LPS) mediated acute lung injury (ALI) are still unresolved. We have previously reported that the disruption of the endothelial barrier is due, at least in part, to the uncoupling of endothelial nitric oxide synthase (eNOS) and increased peroxynitrite-mediated nitration of RhoA. The purpose of this study was to elucidate the molecular mechanisms by which LPS induces eNOS uncoupling during ALI.

Pulmonary artery smooth muscle cell hyperproliferation and metabolic shift triggered by pulmonary overcirculation.

Vascular cell hyperproliferation and metabolic reprogramming contribute to the pathophysiology of pulmonary arterial hypertension (PAH). An important cause of PAH in children with congenital heart disease (CHD) is increased pulmonary blood flow (PBF). To better characterize this disease course we studied early changes in pulmonary artery smooth muscle cell (PASMC) proliferation and metabolism using a unique ovine model of pulmonary overcirculation.

Asymmetric Dimethylarginine Stimulates Akt1 Phosphorylation via Heat Shock Protein 70-Facilitated Carboxyl-Terminal Modulator Protein Degradation in Pulmonary Arterial Endothelial Cells.

Asymmetric dimethylarginine (ADMA) induces the mitochondrial translocation of endothelial nitric oxide synthase (eNOS) through the nitration-mediated activation of Akt1. However, it is recognized that the activation of Akt1 requires phosphorylation events at threonine (T) 308 and serine (S) 473. Thus, the current study was performed to elucidate the potential effect of ADMA on Akt1 phosphorylation and the mechanisms that are involved.

Complex I dysfunction underlies the glycolytic switch in pulmonary hypertensive smooth muscle cells.

ATP is essential for cellular function and is usually produced through oxidative phosphorylation. However, mitochondrial dysfunction is now being recognized as an important contributing factor in the development cardiovascular diseases, such as pulmonary hypertension (PH). In PH there is a metabolic change from oxidative phosphorylation to mainly glycolysis for energy production.