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

2016 ◽  
Vol 130 (20) ◽  
pp. 1837-1839 ◽  
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.

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

2020 ◽  
Author(s):  
Ada Admin ◽  
Mohamed A. Zayed ◽  
Xiaohua Jin ◽  
Chao Yang ◽  
Larisa Belaygorod ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Cell Function ◽  
De Novo ◽  
Lipid Lowering ◽  
Peroxisome Proliferator ◽  
Tubule Formation ◽  
Peroxisome Proliferator Activated Receptor ◽  
Endothelial Cell Function ◽  
Patients With Diabetes

<i>De novo</i> 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).<b> </b>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 <i>Cept1</i> in the endothelium, we engineered a conditional endothelial cell (EC)-specific deletion of <i>Cept1</i> via induced <i>VE-cadherin-CreERT2 </i>mediated recombination (<i>Cept1Lp/LpCre+</i>). <i>Cept1Lp/LpCre+</i> ECs demonstrated decreased proliferation, migration, and tubule formation, and <i>Cept1Lp/LpCre+</i> 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. <i>Cept1</i> esiRNA decreased PPARα-phosphorylation in ECs, which was rescued with fenofibrate but not PC16:0/18:1. Unlike <i>Cept1Lp/LpCre+</i>, <i>Cept1Lp/LpCre+Ppara-/-</i> mice did not demonstrate hind-paw perfusion recovery after feeding fenofibrate.<b> </b>Therefore we demonstrate that CEPT1 is essential for EC function and tissue recovery following ischemia, and that fenofibrate rescues CEPT1-mediated activation of PPARα.

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

2020 ◽  
Author(s):  
Ada Admin ◽  
Mohamed A. Zayed ◽  
Xiaohua Jin ◽  
Chao Yang ◽  
Larisa Belaygorod ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Cell Function ◽  
De Novo ◽  
Lipid Lowering ◽  
Peroxisome Proliferator ◽  
Tubule Formation ◽  
Peroxisome Proliferator Activated Receptor ◽  
Endothelial Cell Function ◽  
Patients With Diabetes

<i>De novo</i> 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).<b> </b>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 <i>Cept1</i> in the endothelium, we engineered a conditional endothelial cell (EC)-specific deletion of <i>Cept1</i> via induced <i>VE-cadherin-CreERT2 </i>mediated recombination (<i>Cept1Lp/LpCre+</i>). <i>Cept1Lp/LpCre+</i> ECs demonstrated decreased proliferation, migration, and tubule formation, and <i>Cept1Lp/LpCre+</i> 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. <i>Cept1</i> esiRNA decreased PPARα-phosphorylation in ECs, which was rescued with fenofibrate but not PC16:0/18:1. Unlike <i>Cept1Lp/LpCre+</i>, <i>Cept1Lp/LpCre+Ppara-/-</i> mice did not demonstrate hind-paw perfusion recovery after feeding fenofibrate.<b> </b>Therefore we demonstrate that CEPT1 is essential for EC function and tissue recovery following ischemia, and that fenofibrate rescues CEPT1-mediated activation of PPARα.

scholarly journals Vascular adaptation in pregnancy and endothelial dysfunction in preeclampsia

2017 ◽  
Vol 232 (1) ◽  
pp. R27-R44 ◽  
Author(s):  
D S Boeldt ◽  
I M Bird
Keyword(s):  
Endothelial Cell ◽  
Endothelial Dysfunction ◽  
Cell Function ◽  
Endothelial Cell Dysfunction ◽  
Hypertensive Disorders Of Pregnancy ◽  
Endothelial Cell Function ◽  
Vascular Adaptation ◽  
Cell Dysfunction ◽  
Maternal Adaptation ◽  
Flow Through

Maternal vascular adaptation to pregnancy is critically important to expand the capacity for blood flow through the uteroplacental unit to meet the needs of the developing fetus. Failure of the maternal vasculature to properly adapt can result in hypertensive disorders of pregnancy such as preeclampsia (PE). Herein, we review the endocrinology of maternal adaptation to pregnancy and contrast this with that of PE. Our focus is specifically on those hormones that directly influence endothelial cell function and dysfunction, as endothelial cell dysfunction is a hallmark of PE. A variety of growth factors and cytokines are present in normal vascular adaptation to pregnancy. However, they have also been shown to be circulating at abnormal levels in PE pregnancies. Many of these factors promote endothelial dysfunction when present at abnormal levels by acutely inhibiting key Ca2+ signaling events and chronically promoting the breakdown of endothelial cell–cell contacts. Increasingly, our understanding of how the contributions of the placenta, immune cells, and the endothelium itself promote the endocrine milieu of PE is becoming clearer. We then describe in detail how the complex endocrine environment of PE affects endothelial cell function, why this has contributed to the difficulty in fully understanding and treating this disorder, and how a focus on signaling convergence points of many hormones may be a more successful treatment strategy.

scholarly journals Lack of association between peroxisome proliferator-activated receptor-gamma-2 gene variants and the occurrence of coronary heart disease in patients with diabetes mellitus

2002 ◽  
pp. 545-551 ◽  
Author(s):  
M Bluher ◽  
T Klemm ◽  
T Gerike ◽  
H Krankenberg ◽  
G Schuler ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Risk Factors ◽  
Coronary Heart Disease ◽  
Heart Disease ◽  
Multiple Logistic Regression Analysis ◽  
Peroxisome Proliferator ◽  
Haemoglobin A1c ◽  
Peroxisome Proliferator Activated Receptor ◽  
Patients With Diabetes ◽  
Reduced Risk

OBJECTIVE: Recent evidence indicates that peroxisome proliferator-activated receptor-gamma (PPARgamma) is expressed at high levels in foam cells of atherosclerotic lesions, that PPARgamma agonists may directly modulate vessel wall function and that mutations in the PPARgamma-2 gene are associated with a reduced risk of coronary artery disease. METHODS: We investigated whether known variants in the PPARgamma-2 gene are associated with the occurrence of coronary heart disease (CHD) in 365 patients with type 2 diabetes, prospectively characterised for the presence or absence of CHD. The Pro115Gln, Pro12Ala, Pro467Leu, Val290Met mutations and two polymorphisms C478T and C161T of the PPARgamma-2 gene were examined using PCR, denaturing gradient gel electrophoresis and direct sequencing. RESULTS: The distribution of the Pro12Ala, Ala12Ala, C161T and T161T variants was not significantly different between patients with and without CHD, independent of the gender. The Pro12Ala (P=0.011) and the Ala12Ala (P=0.006) variant were associated with a higher body mass index (BMI) compared with the Pro12Pro genotype. A multiple logistic regression analysis introducing the typical risk factors for CHD (age, sex, hypertension, smoking, BMI >26 kg/m2, elevated low density lipoprotein cholesterol and haemoglobin A1c >7%) identified age >60, male gender, hypertension and a higher BMI, but not the PPARgamma-2 variants, as significant risk factors for CHD in our study groups. CONCLUSION: The PPARgamma-2 genotype was not associated with an increased or reduced risk of the occurrence of CHD and can therefore not be regarded as an independent risk factor for CHD in patients with diabetes mellitus.

scholarly journals Suppression of Peroxisome Proliferator-Activated Receptor γ-Coactivator-1α Normalizes the Glucolipotoxicity-Induced Decreased BETA2/NeuroD Gene Transcription and Improved Glucose Tolerance in Diabetic Rats

Endocrinology ◽  
2009 ◽  
Vol 150 (9) ◽  
pp. 4074-4083 ◽  
Author(s):  
Ji-Won Kim ◽  
Young-Hye You ◽  
Dong-Sik Ham ◽  
Jae-Hyoung Cho ◽  
Seung-Hyun Ko ◽  
...  
Keyword(s):  
Glucose Tolerance ◽  
Receptor Site ◽  
Diabetic Rats ◽  
Peroxisome Proliferator ◽  
Β Cells ◽  
Β Cell ◽  
Peroxisome Proliferator Activated Receptor ◽  
Cell Dysfunction

Abstract Peroxisome proliferator-activated receptor γ-coactivator-1α (PGC-1α) is significantly elevated in the islets of animal models of diabetes. However, the molecular mechanism has not been clarified. We investigated whether the suppression of PGC-1α expression protects against β-cell dysfunction in vivo and determined the mechanism of action of PGC-1α in β-cells. The studies were performed in glucolipotixicity-induced primary rat islets and INS-1 cells. In vitro and in vivo approaches using adenoviruses were used to evaluate the role of PGC-1α in glucolipotoxicity-associated β-cell dysfunction. The expression of PGC-1α in cultured β-cells increased gradually with glucolipotoxicity. The overexpression of PGC-1α also suppressed the expression of the insulin and β-cell E-box transcription factor (BETA2/NeuroD) genes, which was reversed by PGC-1α small interfering RNA (siRNA). BETA2/NeuroD, p300-enhanced BETA2/NeuroD, and insulin transcriptional activities were significantly suppressed by Ad-PGC-1α but were rescued by Ad-siPGC-1α. PGC-1α binding at the glucocorticoid receptor site on the BETA2/NeuroD promoter increased in the presence of PGC-1α. Ad-siPGC-1α injection through the celiac arteries of 90% pancreatectomized diabetic rats improved their glucose tolerance and maintained their fasting insulin levels. The suppression of PGC-1α expression protects the glucolipotoxicity-induced β-cell dysfunction in vivo and in vitro. A better understanding of the functions of molecules such as PGC-1α, which play key roles in intracellular fuel regulation, could herald a new era of the treatment of patients with type 2 diabetes mellitus by providing protection from glucolipotoxicity, which is an important cause of the development and progression of the disease.

scholarly journals Conjugated linoleic acids attenuate FSH- and IGF1-stimulated cell proliferation; IGF1, GATA4, and aromatase expression; and estradiol-17β production in buffalo granulosa cells involving PPARγ, PTEN, and PI3K/Akt

Reproduction ◽  
2012 ◽  
Vol 144 (3) ◽  
pp. 373-383 ◽  
Author(s):  
Isha Sharma ◽  
Dheer Singh
Keyword(s):  
Cell Proliferation ◽  
Granulosa Cell ◽  
Granulosa Cells ◽  
Cell Function ◽  
Endocrine System ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Beneficial Effects ◽  
Tensin Homolog ◽  
Estradiol 17Β

Conjugated linoleic acid (CLA) has drawn much interest in last two decades in the area ranging from anticancer activity to obesity. A number of research papers have been published recently with regard to CLA's additional biological functions as reproductive benefits. However, not much is known how this mixture of isomeric compounds mediates its beneficial effects particularly on fertility. In this study, we demonstrated the cross talk between downstream signaling of CLA and important hormone regulators of endocrine system, i.e. FSH and IGF1, on buffalo granulosa cell function (proliferation and steroidogenesis). Experiments were performed in primary serum-free buffalo granulosa cell culture, where cells were incubated with CLA in combination with FSH (25 ng/ml) and IGF1 (50 ng/ml). Results showed that 10 μM CLA inhibits FSH- and IGF1-induced granulosa cell proliferation; aromatase,GATA4, andIGF1mRNA; and estradiol-17β production. Western blot analysis of total cell lysates revealed that CLA intervenes the IGF1 signaling by decreasing p-Akt. In addition, CLA was found to upregulate peroxisome proliferator-activated receptor-gamma (PPARG) and phosphatase and tensin homolog (PTEN) level in granulosa cells. Further study using PPARG- and PTEN-specific inhibitors supports the potential role of CLA in granulosa cell proliferation and steroidogenesis involving PPARG, PTEN, and PI3K/Akt pathway.

Abstract 310: Deoxycorticosterone Acetate (doca)-salt Exacerbates Hypertension and Vascular Dysfunction in Mice Expressing Dominant Negative Peroxisome Proliferator-activated Receptor-gamma (pparg) in Smooth Muscle

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Pimonrat Ketsawatsomkron ◽  
Deborah R Davis ◽  
Aline M Hilzendeger ◽  
Justin L Grobe ◽  
Curt D Sigmund
Keyword(s):  
Blood Pressure ◽  
Smooth Muscle ◽  
Transgenic Mice ◽  
Vascular Function ◽  
Vascular Dysfunction ◽  
Critical Role ◽  
Surrogate Marker ◽  
Dominant Negative ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor

PPARG, a ligand-activated transcription factor plays a critical role in the regulation of blood pressure and vascular function. We hypothesized that smooth muscle cell (SMC) PPARG protects against hypertension (HT) and resistance vessel dysfunction. Transgenic mice expressing dominant negative PPARG (S-P467L) in SMC or non-transgenic controls (NT) were implanted with DOCA pellet and allowed ad libitum access to 0.15 M NaCl for 21 days in addition to regular chow and water. Blood pressure was monitored by telemetry and mesenteric arterial (MA) function was assessed by pressurized myograph. At baseline, 24-hour mean arterial pressure (MAP) was similar between NT and S-P467L mice, while the transgenic mice were tachycardic. DOCA-salt increased MAP to a much greater degree in S-P467L mice (Δ MAP; S-P467L: +34.2±6.0, NT: +13.3±5.7, p<0.05 vs NT). Heart rate was similarly decreased in both groups after DOCA-salt. Vasoconstriction to KCl, phenylephrine and endothelin-1 did not differ in MA from DOCA-salt treated NT and S-P467L, while the response to vasopressin was significantly reduced in S-P467L after DOCA-salt (% constriction at 10-8 M, S-P467L: 31.6±5.6, NT: 46.7±3.8, p<0.05 vs NT). Urinary copeptin, a surrogate marker for arginine vasopressin was similar in both groups regardless of treatment. Vasorelaxation to acetylcholine was slightly impaired in S-P467L MA compared to NT at baseline whereas this effect was further exaggerated after DOCA-salt (% relaxation at 10-5 M, S-P467L: 56.1±8.3, NT: 79.4±5.6, p<0.05 vs NT). Vascular morphology at luminal pressure of 75 mmHg showed a significant increase in wall thickness (S-P467L: 18.7±0.8, NT: 16.0±0.4, p<0.05 vs NT) and % media/lumen (S-P467L: 8.4±0.3, NT: 7.1±0.2, p<0.05 vs NT) in S-P467L MA after DOCA-salt. Expression of tissue inhibitor of metalloproteinases (TIMP)-4 and regulator of G-protein signaling (RGS)-5 transcript were 2- and 3.5-fold increased, respectively, in MA of NT with DOCA-salt compared to NT baseline. However, this induction was markedly blunted in S-P467L MA. We conclude that interference with PPARG function in SMC leads to altered gene expression crucial for normal vascular homeostasis, thereby sensitizing the mice to the effects of DOCA-salt induced HT and vascular dysfunction.

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