Mechanisms of Lipid Accumulation in the Bone Morphogenetic Protein Receptor Type 2 Mutant Right Ventricle

Talati, Megha; Brittain, Evan L.; Fessel, Joshua P.; Penner, Niki; Atkinson, James R.; Funke, Mitch; Grueter, Carrie A.; Jerome, W. Gray; Freeman, Michael L.; Newman, John H.; West, James; Hemnes, Anna R.

doi:10.1164/rccm.201507-1444oc

Cited by 86 publications

(102 citation statements)

References 55 publications

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“…CD36 is the main fatty acid transporter in myocardium and accounts for approximately 70% of fatty acid uptake into contracting cardiomyocytes . Our study found that CD36 expression was significantly up‐regulated in lungs and hearts of MCT‐induced PAH, which was consistent with previous studies in the field . Upregulation of CD36 expression increases fatty acid uptake resulting in excess lipid supply and subsequent lipid accumulation in lung and heart which can induce cardiac hypertrophy and contractile dysfunction.…”

Section: Discussionsupporting

confidence: 90%

“…28 Our study found that CD36 expression was significantly up-regulated in lungs and hearts of MCT-induced PAH, which was consistent with previous studies in the field. 29,30 Upregulation of CD36 expression increases fatty acid uptake resulting in excess lipid supply and subsequent lipid accumulation in lung and heart which can induce cardiac hypertrophy and contractile dysfunction. Studies have found that palmitic acid increases CD36 expression, and palmitoylation results in abnormal lipid accumulation in cells.…”

Section: Discussionmentioning

confidence: 99%

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Metabolomics reveals metabolite changes of patients with pulmonary arterial hypertension in China

Chen

Luo

et al. 2020

J Cellular Molecular Medi

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The specific mechanism of pulmonary arterial hypertension (PAH) remains elusive. The present study aimed to explore the underlying mechanism of PAH through the identity of novel biomarkers for PAH using metabolomics approach. Serum samples from 40 patients with idiopathic PAH (IPAH), 20 patients with congenital heart disease‐associated PAH (CHD‐PAH) and 20 healthy controls were collected and analysed by ultra‐high‐performance liquid chromatography coupled with high‐resolution mass spectrometry (UPLC‐HRMS). Orthogonal partial least square‐discriminate analysis (OPLS‐DA) was applied to screen potential biomarkers. These results were validated in monocrotaline (MCT)‐induced PAH rat model. The OPLS‐DA model was successful in screening distinct metabolite signatures which distinguished IPAH and CHD‐PAH patients from healthy controls, respectively (26 and 15 metabolites). Unbiased analysis from OPLS‐DA identified 31 metabolites from PAH patients which were differentially regulated compared to the healthy controls. Our analysis showed dysregulation of the different metabolic pathways, including lipid metabolism, glucose metabolism, amino acid metabolism and phospholipid metabolism pathways in PAH patients compared to their healthy counterpart. Among these metabolites from dysregulated metabolic pathways, a panel of metabolites from lipid metabolism and fatty acid oxidation (lysophosphatidylcholine, phosphatidylcholine, perillic acid, palmitoleic acid, N‐acetylcholine‐d‐sphingomyelin, oleic acid, palmitic acid and 2‐Octenoylcarnitine metabolites) were found to have a close association with PAH. The results from the analysis of both real‐time quantitative PCR and Western blot showed that expression of LDHA, CD36, FASN, PDK1 GLUT1 and CPT‐1 in right heart/lung were significantly up‐regulated in MCT group than the control group.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Metabolomics reveals metabolite changes of patients with pulmonary arterial hypertension in China

Chen

Luo

et al. 2020

J Cellular Molecular Medi

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“…In addition to the above studies related to general metabolism in PAH, there is growing data that the RV in living humans with PAH have altered metabolism. In addition to increased glucose uptake measured by [ 18 F]DG PET (Bokhari et al, 2011), Brittain has also demonstrated increased RV lipid content consistent with lipotoxicity in living humans with PAH , confirming the previously mentioned animal studies Graham et al, 2015;Hemnes et al, 2014;Talati et al, 2016).…”

Section: Translational Studiessupporting

confidence: 76%

Metabolic syndrome, neurohumoral modulation, and pulmonary arterial hypertension

Maron

Leopold

Hemnes

2020

British J Pharmacology

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Pulmonary vascular disease, including pulmonary arterial hypertension (PAH), is increasingly recognized to be affected by systemic alterations including up‐regulation of the renin‐angiotensin‐aldosterone system and perturbations to metabolic pathways, particularly glucose and fat metabolism. There is increasing preclinical and clinical data that each of these pathways can promote pulmonary vascular disease and right heart failure and are not simply disease markers. More recently, trials of therapeutics aimed at neurohormonal activation or metabolic dysfunction are beginning to shed light on how interventions in these pathways may affect patients with PAH. This review will focus on underlying mechanistic data that supports neurohormonal activation and metabolic dysfunction in the pathogenesis of PAH and right heart failure as well as discussing early translational data in patients with PAH.

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“…It is therefore intriguing that we observed more lipid-related abnormalities in PAH in a pattern of IR, thereby yielding potentially novel metabolic insight into this disorder. Emerging literature suggests that lipids are abnormally metabolized in PAH patients, with elevated plasma FFAs (5), reduced HDL (19), ectopic lipid deposition in the skeletal muscle, and a possible cardiac lipotoxic phenotype (5,36,37). When using the standard TG/HDL ratio, 90% of our patients were IR, while only about half of the metabolic-syndrome-matched controls were (P < 0.05), which matched the frequency of IR using glucose and insulin-based metrics such as the HOMA-IR in controls.…”

Section: L I N I C a L M E D I C I N Ementioning

confidence: 99%

Human PAH is characterized by a pattern of lipid-related insulin resistance

Hemnes¹,

Luther²,

Rhodes³

et al. 2019

JCI Insight

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IntroductionPulmonary arterial hypertension (PAH) is a life-limiting condition characterized by progressive vascular obliteration leading to right heart failure and ultimately death. Recent research has highlighted altered cellular and systemic metabolism as a key feature promoting pulmonary vascular disease and right heart BACKGROUND. Pulmonary arterial hypertension (PAH) is a deadly disease of the small pulmonary vasculature with an increased prevalence of insulin resistance (IR). Insulin regulates both glucose and lipid homeostasis. We sought to quantify glucose-and lipid-related IR in human PAH, testing the hypothesis that lipoprotein indices are more sensitive indices of IR in PAH. METHODS.Oral glucose tolerance testing in PAH patients and triglyceride-matched (TG-matched) controls and proteomic, metabolomics, and lipoprotein analyses were performed in PAH and controls. Results were validated in an external cohort and in explanted human PAH lungs. RESULTS. PAH patients were similarly glucose intolerant or IR by glucose homeostasis metrics compared with control patients when matched for the metabolic syndrome. Using the insulinsensitive lipoprotein index, TG/HDL ratio, PAH patients were more commonly IR than controls. Proteomic and metabolomic analysis demonstrated separation between PAH and controls, driven by differences in lipid species. We observed a significant increase in long-chain acylcarnitines, phosphatidylcholines, insulin metabolism-related proteins, and in oxidized LDL receptor 1 (OLR1) in PAH plasma in both a discovery and validation cohort. PAH patients had higher lipoprotein axis-related IR and lipoprotein-based inflammation scores compared with controls. PAH patient lung tissue showed enhanced OLR1 immunostaining within plexiform lesions and oxidized LDL accumulation within macrophages.CONCLUSIONS. IR in PAH is characterized by alterations in lipid and lipoprotein homeostasis axes, manifest by elevated TG/HDL ratio, and elevated circulating medium-and long-chain acylcarnitines and lipoproteins. Oxidized LDL and its receptor OLR1 may play a role in a proinflammatory phenotype in PAH.

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Mechanisms of Lipid Accumulation in the Bone Morphogenetic Protein Receptor Type 2 Mutant Right Ventricle

Cited by 86 publications

References 55 publications

Metabolomics reveals metabolite changes of patients with pulmonary arterial hypertension in China

Metabolomics reveals metabolite changes of patients with pulmonary arterial hypertension in China

Metabolic syndrome, neurohumoral modulation, and pulmonary arterial hypertension

Human PAH is characterized by a pattern of lipid-related insulin resistance

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