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King, George

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King

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George

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King, George
Author's Publications: search.filters.isAuthorOfPublication.117a47eb-a6a1-41ef-af84-3e340466d94b

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    Overexpressing IRS1 in Endothelial Cells Enhances Angioblast Differentiation and Wound Healing in Diabetes and Insulin Resistance
    (American Diabetes Association, 2016) Katagiri, Sayaka; Park, Kyoungmin; Maeda, Yasutaka; Rao, Tata Nageswara; Khamaisi, Mogher; Li, Qian; Yokomizo, Hisashi; Mima, Akira; Lancerotto, Luca; Wagers, Amy; Orgill, Dennis; King, George
    The effect of enhancing insulin’s actions in endothelial cells (ECs) to improve angiogenesis and wound healing was studied in obesity and diabetes. Insulin receptor substrate 1 (IRS1) was overexpressed in ECs using the VE-cadherin promoter to create ECIRS1 TG mice, which elevated pAkt activation and expressions of vascular endothelial growth factor (VEGF), Flk1, and VE-cadherin in ECs and granulation tissues (GTs) of full-thickness wounds. Open wound and epithelialization rates and angiogenesis significantly improved in normal mice and high fat (HF) diet–induced diabetic mice with hyperinsulinemia in ECIRS1 TG versus wild type (WT), but not in insulin-deficient diabetic mice. Increased angioblasts and EC numbers in GT of ECIRS1 mice were due to proliferation in situ rather than uptake. GT in HF-fed diabetic mice exhibited parallel decreases in insulin and VEGF-induced pAkt and EC numbers by >50% without changes in angioblasts versus WT mice, which were improved in ECIRS1 TG mice on normal chow or HF diet. Thus, HF-induced diabetes impaired angiogenesis by inhibiting insulin signaling in GT to decrease the differentiation of angioblasts to EC, which was normalized by enhancing insulin’s action targeted to EC, a potential target to improve wound healing in diabetes and obesity.
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    High density lipoprotein modulates osteocalcin expression in circulating monocytes: a potential protective mechanism for cardiovascular disease in type 1 diabetes
    (BioMed Central, 2017) Maddaloni, Ernesto; Xia, Yu; Park, Kyoungmin; D’Eon, Stephanie; Tinsley, Liane J.; St-Louis, Ronald; Khamaisi, Mogher; Li, Qian; King, George; Keenan, Hillary A.
    Background: Cardiovascular disease (CVD) is a major cause of mortality in type 1 diabetes (T1D). A pro-calcific drift of circulating monocytes has been linked to vascular calcification and is marked by the surface expression of osteocalcin (OCN). We studied OCN+ monocytes in a unique population with ≥50 years of T1D, the 50-Year Joslin Medalists (J50M). Methods: CD45 bright/CD14+/OCN+ cells in the circulating mononuclear blood cell fraction were quantified by flow cytometry and reported as percentage of CD45 bright cells. Mechanisms were studied by inducing OCN expression in human monocytes in vitro. Results: Subjects without history of CVD (n = 16) showed lower levels of OCN+ monocytes than subjects with CVD (n = 14) (13.1 ± 8.4% vs 19.9 ± 6.4%, p = 0.02). OCN+ monocytes level was inversely related to total high density lipoprotein (HDL) cholesterol levels (r = −0.424, p = 0.02), large (r = −0.413, p = 0.02) and intermediate (r = −0.445, p = 0.01) HDL sub-fractions, but not to small HDL. In vitro, incubation with OxLDL significantly increased the number of OCN+ monocytes (p < 0.01). This action of OxLDL was significantly reduced by the addition of HDL in a concentration dependent manner (p < 0.001). Inhibition of the scavenger receptor B1 reduced the effects of both OxLDL and HDL (p < 0.05). Conclusions: Low OCN+ monocytes levels are associated with lack of CVD in people with long duration T1D. A possible mechanism for the increased OCN+ monocytes could be the elevated levels of oxidized lipids due to diabetes which may be inhibited by HDL. These findings suggest that circulating OCN+ monocytes could be a marker for vascular disease in diabetic patients and possibly modified by HDL elevation. Electronic supplementary material The online version of this article (doi:10.1186/s12933-017-0599-2) contains supplementary material, which is available to authorized users.
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    Protective Effects of GLP-1 on Glomerular Endothelium and Its Inhibition by PKCβ Activation in Diabetes
    (American Diabetes Association, 2012) Mima, Akira; Hiraoka-Yamomoto, Junko; Li, Qian; Kitada, Munehiro; Li, Chenzhong; Geraldes, Pedro; Matsumoto, Motonobu; Mizutani, Koji; Park, Kyoungmin; Cahill, Christopher; Nishikawa, Shin-Ichi; Rask-Madsen, Christian; King, George
    To characterize glucagon-like peptide (GLP)-1 signaling and its effect on renal endothelial dysfunction and glomerulopathy. We studied the expression and signaling of GLP-1 receptor (GLP-1R) on glomerular endothelial cells and the novel finding of protein kinase A–dependent phosphorylation of c-Raf at Ser259 and its inhibition of angiotensin II (Ang II) phospho–c-Raf(Ser338) and Erk1/2 phosphorylation. Mice overexpressing protein kinase C (PKC)β2 in endothelial cells (EC-PKCβ2Tg) were established. Ang II and GLP-1 actions in glomerular endothelial cells were analyzed with small interfering RNA of GLP-1R. PKCβ isoform activation induced by diabetes decreased GLP-1R expression and protective action on the renal endothelium by increasing its degradation via ubiquitination and enhancing phospho–c-Raf(Ser338) and Ang II activation of phospho-Erk1/2. EC-PKCβ2Tg mice exhibited decreased GLP-1R expression and increased phospho–c-Raf(Ser338), leading to enhanced effects of Ang II. Diabetic EC-PKCβ2Tg mice exhibited greater loss of endothelial GLP-1R expression and exendin-4–protective actions and exhibited more albuminuria and mesangial expansion than diabetic controls. These results showed that the renal protective effects of GLP-1 were mediated via the inhibition of Ang II actions on cRaf(Ser259) and diminished by diabetes because of PKCβ activation and the increased degradation of GLP-1R in the glomerular endothelial cells.
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    Improvement of Insulin Sensitivity by Isoenergy High Carbohydrate Traditional Asian Diet: A Randomized Controlled Pilot Feasibility Study
    (Public Library of Science, 2014) Hsu, William; Lau, Ka Hei Karen; Matsumoto, Motonobu; Moghazy, Dalia; Keenan, Hillary; King, George
    The prevalence of diabetes is rising dramatically among Asians, with increased consumption of the typical Western diet as one possible cause. We explored the metabolic responses in East Asian Americans (AA) and Caucasian Americans (CA) when transitioning from a traditional Asian diet (TAD) to a typical Western diet (TWD), which has not been reported before. This 16-week randomized control pilot feasibility study, included 28AA and 22CA who were at risk of developing type 2 diabetes. Eight weeks of TAD were provided to all participants, followed by 8 weeks of isoenergy TWD (intervention) or TAD (control). Anthropometric measures, lipid profile, insulin resistance and inflammatory markers were assessed. While on TAD, both AA and CA improved in insulin AUC (−960.2 µU/mL×h, P = 0.001) and reduced in weight (−1.6 kg; P<0.001), body fat (−1.7%, P<0.001) and trunk fat (−2.2%, P<0.001). Comparing changes from TAD to TWD, AA had a smaller weight gain (−1.8 to 0.3 kg, P<0.001) than CA (−1.4 to 0.9 kg, P = 0.001), but a greater increase in insulin AUC (AA: −1402.4 to 606.2 µU/mL×h, P = 0.015 vs CA: −466.0 to 223.5 µU/mL×h, P = 0.034) and homeostatic static model assessment-insulin resistance (HOMA-IR) (AA: −0.3 to 0.2, P = 0.042 vs CA: −0.1 to 0.0, P = 0.221). Despite efforts to maintain isoenergy state and consumption of similar energy, TAD induced weight loss and improved insulin sensitivity in both groups, while TWD worsened the metabolic profile. Trial Registration: ClinicalTrials.gov NCT00379548
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    Sexual Dysfunction as a Marker of Cardiovascular Disease in Males With 50 or More Years of Type 1 Diabetes
    (American Diabetes Association, 2013) Turek, Sara J.; Hastings, Stephanie M.; Sun, Jennifer; King, George; Keenan, Hillary
    OBJECTIVE Vascular dysfunction is a major contributor to diabetes complications. It is also the primary physiologic cause of erectile dysfunction and considered an independent predictor of cardiovascular disease (CVD) in males over age 40 years. A cohort of individuals with 50 or more years of type 1 diabetes, Joslin Medalists, have low rates of small but not large vessel complications. This study aims to identify the prevalence and longitudinal association of sexual dysfunction (SD) with CVD in Joslin Medalists. RESEARCH DESIGN AND METHODS Description and association of self-assessment of SD in males of the Medalist cohort by self-reported sexual problems with CVD. SD is validated through the use of the abbreviated International Index of Erectile Dysfunction (IIEF). RESULTS Of 301 males in the Medalist Study, 69.8% reported a history of SD. Unadjusted risk factors included elevated glycated hemoglobin (HbA1c) (P = 0.02), elevated BMI (P = 0.03), higher total cholesterol (P = 0.02), lower HDL (P < 0.01), and increased levels of interleukin-6 (P = 0.03). SD was independently associated with CVD (age-, HbA1c-, and BMI-adjusted OR 1.9 [95% CI 1.0–3.5]). In adjusted analyses, retinal, neural, and renal complications were not associated (P > 0.05) with SD. Current report of SD (IIEF score ≤17) in a subset of Medalists was significantly correlated with self-reported longitudinal SD. CONCLUSIONS SD in those with extreme-duration type 1 diabetes is independently associated with CVD, representing a large-vessel pattern. The findings suggest that SD may predict CVD in those with type 1 diabetes of long duration. These individuals have also been found to be relatively free of microvascular complications.
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    Characterization of protein kinase C isoform's action on retinoblastoma protein phosphorylation, vascular endothelial growth factor-induced endothelial cell proliferation, and retinal neovascularization
    (Proceedings of the National Academy of Sciences, 2002) Suzuma, K.; Takahara, N.; Suzuma, I.; Isshiki, K.; Ueki, K.; Leitges, M.; Aiello, Lloyd; King, George
    Retinal neovascularization is a major cause of blindness and requires the activities of several signaling pathways and multiple cytokines. Activation of protein kinase C (PKC) enhances the angiogenic process and is involved in the signaling of vascular endothelial growth factor (VEGF). We have demonstrated a dramatic increase in the angiogenic response to oxygen-induced retinal ischemia in transgenic mice overexpressing PKCβ2 isoform and a significant decrease in retinal neovascularization in PKCβ isoform null mice. The mitogenic action of VEGF, a potent hypoxia-induced angiogenic factor, was increased by 2-fold in retinal endothelial cells by the overexpression of PKCβ1 or β2 isoforms and inhibited significantly by the overexpression of a dominant-negative PKCβ2 isoform but not by the expression of PKC α, δ, and ζ isoforms. Association of PKCβ2 isoform with retinoblastoma protein was discovered in retinal endothelial cells, and PKCβ2 isoform increased retinoblastoma phosphorylation under basal and VEGF-stimulated conditions. The potential functional consequences of PKCβ-induced retinoblastoma phosphorylation could include enhanced E2 promoter binding factor transcriptional activity and increased VEGF-induced endothelial cell proliferation.
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    Differential Effects of Bactericidal/Permeability-Increasing Protein (BPI) Analogues on Retinal Neovascularization and Retinal Pericyte Growth
    (Association for Research in Vision and Ophthalmology, 2002) Rauniyar, Ravi; Suzuma, Kiyoshi; King, Adam L.; Aiello, Lloyd; King, George
    Purpose. Bactericidal/permeability-increasing protein (BPI), an antibacterial and lipopolysaccharide-neutralizing protein, also has an antiangiogenic effect. To evaluate the therapeutic role of BPI in ischemic retinopathies, the antiangiogenic activity of a human recombinant 21-kDa modified N-terminal fragment of BPI (rBPI21), which has the biological properties of the holoprotein, and a peptidomimetic (XMP.Z) derived from BPI were examined. Methods. The effects of rBPI21 and XMP.Z on VEGF-induced growth of bovine retinal microvascular endothelial cells (BRECs) and on serum-induced growth of bovine retinal pericytes (BRPs) and retinal pigment epithelial cells (BRPECs) were evaluated by determining total DNA content. The neonatal mouse model of retinopathy of prematurity (ROP) was used to study the effect of XMP.Z in vivo. Intraperitoneal injections of the peptidomimetic (10 mg/kg) were administered every 24 hours for 5 days (postnatal [P]12–P17) during induction of neovascularization. Retinal neovascularization was evaluated using flatmounts of fluorescein-dextran–perfused retinas and quantitated by counting retinal cell nuclei anterior to the internal limiting membrane. Results. VEGF (25 ng/mL) increased the total DNA per well of BRECs by 120% ± 50% (P < 0.001), which was inhibited by addition of rBPI21 or XMP.Z, with decreases of 77% ± 15% (P < 0.05) and 107% ± 19% (P < 0.01) at maximum effective doses of 75 and 15μ g/mL rBPI21 and XMP.Z, respectively. In contrast, rBPI21 at 75 μg/mL enhanced the total DNA per well of BRP 53% ± 14% (P < 0.001) in the presence of 5% fetal bovine serum (FBS), whereas XMP.Z enhanced BRP growth by 27% ± 7% (P < 0.001) at 5 μg/mL. In the presence of 10% FBS, rBPI21 and XMP.Z increased BRP growth by 91% ± 35% (P < 0.001) and 43% ± 18% (P < 0.01), respectively. In the oxygen-induced ROP neonatal mouse model, retinal neovascularization was decreased by 40% ± 16% (n = 5, P < 0.01) when animals were treated with XMP.Z. Conclusions. Two BPI-derived compounds, rBPI21 and XMP.Z, significantly suppressed VEGF-induced BREC growth in vitro, while conversely enhancing the growth of BRPs, even above that induced by 20% FBS. When tested in animals, XMP.Z also suppressed ischemia-induced retinal neovascularization in mice. These data suggest that BPI-derived compounds may have unique therapeutic potential for proliferative retinal diseases such as diabetic retinopathy, if physiological levels can be achieved in clinical settings.
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    Activation of PKC-δ and SHP-1 by hyperglycemia causes vascular cell apoptosis and diabetic retinopathy
    (Nature Publishing Group, 2009) Geraldes, Pedro; Hiraoka-Yamamoto, Junko; Matsumoto, Motonobu; Clermont, Allen; Leitges, Michael; Marette, Andre; Aiello, Lloyd; Kern, Timothy S; King, George
    Cellular apoptosis induced by hyperglycemia occurs in many vascular cells and is crucial for the initiation of diabetic pathologies. In the retina, pericyte apoptosis and the formation of acellular capillaries, the most specific vascular pathologies attributed to hyperglycemia, is linked to the loss of platelet-derived growth factor (PDGF)-mediated survival actions owing to unknown mechanisms. Here we show that hyperglycemia persistently activates protein kinase C-delta (PKC-delta, encoded by Prkcd) and p38alpha mitogen-activated protein kinase (MAPK) to increase the expression of a previously unknown target of PKC-delta signaling, Src homology-2 domain-containing phosphatase-1 (SHP-1), a protein tyrosine phosphatase. This signaling cascade leads to PDGF receptor-beta dephosphorylation and a reduction in downstream signaling from this receptor, resulting in pericyte apoptosis independently of nuclear factor-kappaB (NF-kappaB) signaling. We observed increased PKC-delta activity and an increase in the number of acellular capillaries in diabetic mouse retinas, which were not reversible with insulin treatment that achieved normoglycemia. Unlike diabetic age-matched wild-type mice, diabetic Prkcd(-/-) mice did not show activation of p38alpha MAPK or SHP-1, inhibition of PDGF signaling in vascular cells or the presence of acellular capillaries. We also observed PKC-delta, p38alpha MAPK and SHP-1 activation in brain pericytes and in the renal cortex of diabetic mice. These findings elucidate a new signaling pathway by which hyperglycemia can induce PDGF resistance and increase vascular cell apoptosis to cause diabetic vascular complications.
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    Loss of Insulin Signaling in Vascular Endothelial Cells Accelerates Atherosclerosis in Apolipoprotein E Null Mice
    (Elsevier BV, 2010) Rask-Madsen, Christian; Li, Qian; Freund, Bryn; Feather, Danielle; Abramov, Roman; Wu, I-Hsien; Chen, Kai; Yamamoto-Hiraoka, Junko; Goldenbogen, Jan; Sotiropoulos, Konstantinos B.; Clermont, Allen; Geraldes, Pedro; Dall, Claudia; Wagers, Amy; Huang, Paul; Rekhter, Mark; Scalia, Rosario; Kahn, C.; King, George
    To determine whether insulin action on endothelial cells promotes or protects against atherosclerosis, we generated apolipoprotein E null mice in which the insulin receptor gene was intact or conditionally deleted in vascular endothelial cells. Insulin sensitivity, glucose tolerance, plasma lipids, and blood pressure were not different between the two groups, but atherosclerotic lesion size was more than 2-fold higher in mice lacking endothelial insulin signaling. Endothelium-dependent vasodilation was impaired and endothelial cell VCAM-1 expression was increased in these animals. Adhesion of mononuclear cells to endothelium in vivo was increased 4-fold compared with controls but reduced to below control values by a VCAM-1-blocking antibody. These results provide definitive evidence that loss of insulin signaling in endothelium, in the absence of competing systemic risk factors, accelerates atherosclerosis. Therefore, improving insulin sensitivity in the endothelium of patients with insulin resistance or type 2 diabetes may prevent cardiovascular complications.