CEPT1-Mediated Phospholipogenesis Regulates Endothelial Cell Function and Ischemia-Induced Angiogenesis Through PPARα

De novo phosopholipogenesis, mediated by choline-ethanolamine phosphotransferase 1 (CEPT1), is essential for phospholipid activation of transcription factors such as peroxisome proliferator-activated receptor α (PPARα) in the liver. Fenofibrate, a PPARα agonist and lipid-lowering agent, decreases amputation incidence in patients with diabetes. Since we previously observed that CEPT1 is elevated in carotid plaque of patients with diabetes, we evaluated the role of CEPT1 in peripheral arteries and PPARα-phosphorylation (Ser12). CEPT1 was found to be elevated in diseased lower extremity arterial intima of individuals with peripheral arterial disease and diabetes. To evaluate the role of Cept1 in the endothelium, we engineered a conditional endothelial cell (EC)-specific deletion of Cept1 via induced VE-cadherin-CreERT2 mediated recombination (Cept1Lp/LpCre+). Cept1Lp/LpCre+ ECs demonstrated decreased proliferation, migration, and tubule formation, and Cept1Lp/LpCre+ mice had reduced perfusion and angiogenesis in ischemic hind-limbs. Peripheral ischemic recovery and PPARα signaling was further compromised by Streptozotocin-induced diabetes, and ameliorated by feeding fenofibrate. Cept1 esiRNA decreased PPARα-phosphorylation in ECs, which was rescued with fenofibrate but not PC16:0/18:1. Unlike Cept1Lp/LpCre+, Cept1Lp/LpCre+Ppara-/- mice did not demonstrate hind-paw perfusion recovery after feeding fenofibrate. Therefore we demonstrate that CEPT1 is essential for EC function and tissue recovery following ischemia, and that fenofibrate rescues CEPT1-mediated activation of PPARα.

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Vascular smooth muscle cell dysfunction in diabetes: nuclear receptors channel to relaxation

Clinical Science ◽

10.1042/cs20160518 ◽

2016 ◽

Vol 130 (20) ◽

pp. 1837-1839 ◽

Cited By ~ 1

Author(s):

Geneviève Doyon ◽

Dennis Bruemmer

Keyword(s):

Cell Function ◽

Vascular Dysfunction ◽

Microvascular Disease ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Endothelial Cell Function ◽

Cell Dysfunction ◽

Kv Channels ◽

Voltage Dependent ◽

Patients With Diabetes

Endothelial dysfunction and impaired vascular relaxation represent a common cause of microvascular disease in patients with diabetes. Although multiple mechanisms underlying altered endothelial cell function in diabetes have been described, there is currently no specific and approved pharmacological treatment. In this edition of Clinical Science, Morales-Cano et al. characterize voltage-dependent K+ (Kv) channels as genes regulated by pharmacological activation of peroxisome proliferator-activated receptor-b/d (PPARb/d). Diabetes altered Kv channel function leading to impaired coronary artery relaxation, which was prevented by pharmacological activation of PPARb/d. These studies highlight an important mechanism of vascular dysfunction in diabetes and point to a potential approach for therapy, particularly considering that PPARb/d ligands have been developed and tested in small clinical trials.

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211 IMPROVEMENTS IN ENDOTHELIAL CELL FUNCTION WITH PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR γ LIGAND, ROSIGLITAZONE.

Journal of Investigative Medicine ◽

10.1136/jim-52-suppl1-211 ◽

2004 ◽

Vol 52 (Suppl 1) ◽

pp. S116.2-S116

Author(s):

J Kim ◽

S. Lee ◽

M. Kim ◽

J. Petrofsky ◽

M. Laymon ◽

...

Keyword(s):

Endothelial Cell ◽

Cell Function ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Endothelial Cell Function

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IMPROVEMENTS IN ENDOTHELIAL CELL FUNCTION WITH PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR γ LIGAND, ROSIGLITAZONE.

Journal of Investigative Medicine ◽

10.1097/00042871-200401001-00211 ◽

2004 ◽

Vol 52 ◽

pp. S116

Author(s):

J Kim ◽

S. Lee ◽

M. Kim ◽

J. Petrofsky ◽

M. Laymon ◽

...

Keyword(s):

Endothelial Cell ◽

Cell Function ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Endothelial Cell Function

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Enhanced Vascular Endothelial Cell Function on Nanostructured Titanium Surface Features: The Role of Nano to Submicron Roughness

MRS Proceedings ◽

10.1557/proc-1136-dd04-04 ◽

2008 ◽

Vol 1136 ◽

Cited By ~ 2

Author(s):

Jing Lu ◽

Dongwoo Khang ◽

Thomas J. Webster

Keyword(s):

Cell Adhesion ◽

Endothelial Cell ◽

Cell Function ◽

Vascular Endothelial Cell ◽

Vascular Endothelial ◽

Endothelial Cell Function ◽

Titanium Surfaces ◽

Endothelial Cell Adhesion

ABSTRACTTo study the contribution of different surface feature properties in improving vascular endothelial cell adhesion, rationally designed nano/sub-micron patterns with various dimensions were created on titanium surfaces in this study. In vitro results indicated that endothelial cell adhesion was improved when the titanium pattern dimensions decreased into the nano-scale. Specifically, endothelial cells preferred to adhere on sub-micron and nano rough titanium substrates compared to flat titanium. Moreover, titanium with nano and sub-micron roughness and with the same chemistry as compared to flat titanium, had significantly greater surface energy. Thus, the present study indicated the strong potential of surface nanotopography and nano/sub-micron roughness for improving current vascular stent design.

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FKBPL and SIRT-1, key angiogenesis proteins, are downregulated by diabetes in pregnancy

10.1101/2020.10.06.20208116 ◽

2020 ◽

Cited By ~ 1

Author(s):

Abdelrahim Alqudah ◽

Kelly-Ann Eastwood ◽

Djurdja Jerotic ◽

Naomi Todd ◽

Denise Hoch ◽

...

Keyword(s):

Endothelial Cell ◽

Protein Expression ◽

Gestational Age ◽

High Glucose ◽

Cell Function ◽

First Trimester ◽

Diabetes In Pregnancy ◽

Endothelial Cell Function ◽

In Pregnancy

AbstractContextDiabetes in pregnancy is associated with numerous complications, however the mechanisms are still poorly understood.ObjectiveTo investigate the role of new angiogenesis markers, FKBPL and SIRT-1, in pre-gestational (type 1 diabetes, T1D) and gestational diabetes (GDM).Design and interventionPlacental FKBPL, SIRT-1, PlGF and VEGF-R1 protein expression was determined from pregnant women with GDM or T1D, and in first trimester trophoblast cells exposed to high glucose and varying oxygen concentrations. Endothelial cell function was assessed in high glucose conditions and FKBPL overexpression.Settings and ParticipantsHuman placental samples from pregnant women with GDM (n=6) or T1D (n=8) were collected to assess FKBPL and SIRT-1 protein expression compared to non-diabetic controls.Main outcome measuresTo determine the role of placental FKBPL and/or SIRT-1 in diabetic pregnancies, in first trimester trophoblasts and endothelial cell function in high-glucose environment.ResultsPlacental FKBPL protein expression was downregulated in T1D (FKBPL; p<0.05) whereas PlGF/VEGF-R1 were upregulated (p<0.05); correlations adjusted for gestational age were also significant. In the presence of GDM, only SIRT-1 (p<0.001) was significantly downregulated even when adjusted for gestational age (r=-0.92, p=0.001). FKBPL and SIRT-1 were also downregulated in ACH-3P cells in high glucose conditions and 6.5%/2.5% oxygen concentrations (p<0.05). FKBPL overexpression in HUVECs reduced tubule formation compared to empty vector control, in high glucose conditions (junctions; p<0.01, branches; p<0.05).ConclusionsFKBPL and/or SIRT-1 downregulation in response to diabetes may have a role in the development of vascular dysfunction in pregnancy, and associated complications such as preeclampsia.

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