L-Carnitine preserves endothelial function in a lamb model of increased pulmonary blood flow

Sharma, Shruti; Aramburo, Angela; Rafikov, Ruslan; Sun, Xutong; Kumar, Sanjiv; Oishi, Peter; Datar, Sanjeev A.; Raff, Gary W.; Xoinis, K; Kalkan, Gohkan; Fratz, Sohrab; Fineman, Jeffrey R.; Black, Stephen M.

doi:10.1038/pr.2013.71

Cited by 38 publications

(33 citation statements)

References 43 publications

(58 reference statements)

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“…Therefore, increased levels of carnitine and acylcarnitine may reflect the significant inhibition of mitochondrial fatty acid β‐oxidation during the development of PAH. Burgeoning evidence points towards the metabolic homeostasis of carnitine that is integral in the formation and development of PAH . We also found a significant increase in palmitoleic acid and oleic acid levels in peripheral blood of patients with PAH.…”

Section: Discussionsupporting

confidence: 63%

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: 63%

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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“…This preservation of mitochondrial function correlated with improved hsp90 function, increased NO generation and reduced NOS uncoupling [100]. Most importantly the loss of endothelial dependent vasodilation was prevented [100]. These data confirm the therapeutic possibilities of targeting the mitochondria to prevent the development of pulmonary endothelial dysfunction in children born with CHD that results in increased PBF.…”

Section: The Mitochondrion As a Therapeutic Targetsupporting

confidence: 60%

“…We have recently carried out a prevention trial in which Shunt lambs were treated for 4-weeks with 100 mg/kg/day of L-carnitine or a vehicle. L-Carnitine-treated lambs had increased expression of the carnitine shuttle enzymes CPT1 and CPT2 protein levels, increased CrAT enzyme activity and an improved AC: FC ratio [100]. This preservation of mitochondrial function correlated with improved hsp90 function, increased NO generation and reduced NOS uncoupling [100].…”

Section: The Mitochondrion As a Therapeutic Targetmentioning

confidence: 93%

“…L-Carnitine-treated lambs had increased expression of the carnitine shuttle enzymes CPT1 and CPT2 protein levels, increased CrAT enzyme activity and an improved AC: FC ratio [100]. This preservation of mitochondrial function correlated with improved hsp90 function, increased NO generation and reduced NOS uncoupling [100]. Most importantly the loss of endothelial dependent vasodilation was prevented [100].…”

Section: The Mitochondrion As a Therapeutic Targetmentioning

confidence: 99%

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Mitochondrial Dysfunction and Congenital Heart Disease

Black

Fineman²

2014

Pediat Therapeut

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The pulmonary vasculature in infants born with congenital heart defects that cause increased Pulmonary Blood Flow (PBF) is subjected to pathologic mechanical forces, including chronically increased shear stress, resulting in early functional abnormalities of the vascular endothelium. These functional abnormalities occur prior to the development of well-described morphologic changes. However, little is known about the factors that transduce the abnormal shear forces associated with increased PBF into abnormal vascular function and reactivity. Recently the disruption of mitochondrial function has been identified as a new mechanism that leads to the development of pulmonary endothelial dysfunction. This is a complex process that involves post-translational regulation of multiple proteins and the mitochondrial redistribution of uncoupled endothelial nitric oxide synthase (eNOS) resulting in the disruption of carnitine metabolism and subsequently mitochondrial bioenergetics. As both eNOS and GTP cyclohydrolase I, the rate limiting enzyme in tetrahydrobiopterin (BH4) biosynthesis, are chaperoned by hsp90 this results in a "feed-forward" signaling cascade in which eNOS becomes progressively more uncoupled resulting in pulmonary endothelial dysfunction. This review will discuss the current knowledge in the field, the limitations in our understanding this complex process, and the potential for targeting mitochondrial function in the treatment of children born with congenital heart defects that result in increased pulmonary blood flow.

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“…Inhibition of endothelial CPT1a impairs EC proliferation and activates the endothelial-to-mesenchymal transition, which plays a role in the pathogenesis of pulmonary arterial hypertension, atherosclerosis, and tumor spreading (Schoors et al, 2015;Xiong et al, 2018). On the contrary, stimulation of CPT1 activity by chronic L-carnitine administration improved endothelial function in an animal model of congenital heart defect (Sharma et al, 2013). In light of the crucial role of FAO in maintaining EC quiescence and redox balance, L-carnitine supplementation, by counteracting the age-related decline in CPT1a activity (Gomez et al, 2012), could prove useful to delay the onset of age-related endothelial dysfunction.…”

Section: Therapeutic Interventions Targeting Endothelial Cell Metabolismmentioning

confidence: 99%

Where Metabolism Meets Senescence: Focus on Endothelial Cells

et al. 2019

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Despite the decline in their proliferative potential, senescent cells display a high metabolic activity. Senescent cells have been shown to acquire a more glycolytic state even in presence of high oxygen levels, in a way similar to cancer cells. The diversion of pyruvate, the final product of glycolysis, away from oxidative phosphorylation results in an altered bioenergetic state and may occur as a response to the enhanced oxidative stress caused by the accumulation of dysfunctional mitochondria. This metabolic shift leads to increased AMP/ATP and ADP/ATP ratios, to the subsequent AMPK activation, and ultimately to p53-mediated growth arrest. Mounting evidences suggest that metabolic reprogramming is critical to direct considerable amounts of energy toward specific activities related to the senescent state, including the senescence-associated secretory phenotype (SASP) and the modulation of immune responses within senescent cell tissue microenvironment. Interestingly, despite the relative abundance of oxygen in the vascular compartment, healthy endothelial cells (ECs) produce most of their ATP content from the anaerobic conversion of glucose to lactate. Their high glycolytic rate further increases during senescence. Alterations in EC metabolism have been identified in age-related diseases (ARDs) associated with a dysfunctional vasculature, including atherosclerosis, type 2 diabetes and cardiovascular diseases. In particular, higher production of reactive oxygen species deriving from a variety of enzymatic sources, including uncoupled endothelial nitric oxide synthase and the electron transport chain, causes DNA damage and activates the NAD +-consuming enzymes polyADP-ribose polymerase 1 (PARP1). These non-physiological mechanisms drive the impairment of the glycolytic flux and the diversion of glycolytic intermediates into many pathological pathways. Of note, accumulation of senescent ECs has been reported in the context of ARDs. Through their pro-oxidant, pro-inflammatory, vasoconstrictor, and prothrombotic activities, they negatively impact on vascular physiology, promoting both the onset and development of ARDs. Here, we review the current knowledge on the cellular senescence-related metabolic changes and their contribution to the mechanisms underlying the pathogenesis of ARDs, with a particular focus on ECs. Moreover, current and potential interventions aimed at modulating EC metabolism, in order to prevent or delay ARD onset, will be discussed.

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L-Carnitine preserves endothelial function in a lamb model of increased pulmonary blood flow

Cited by 38 publications

References 43 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

Mitochondrial Dysfunction and Congenital Heart Disease

Where Metabolism Meets Senescence: Focus on Endothelial Cells

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