Regulation of the atherogenic properties of vascular smooth muscle proteoglycans by oral anti-hyperglycemic agents

Dios, Stephanie de; Frontanilla, K V; Nigro, Julie; Ballinger, Mandy L.; Ivey, Melanie E.; Cawson, Elizabeth A; Little, Peter J.

doi:10.1016/j.jdiacomp.2006.03.003

Cited by 32 publications

(26 citation statements)

References 47 publications

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“…These results clearly demonstrate that HA synthesis, but not CS or HS synthesis, is inhibited by both AICAR and metformin. Previous studies showed that metformin does not decrease sulfate incorporation into GAGs (26). However, because HA is not sulfated, our results are novel and particularly interesting because of the critical functions of HA in the vasculature.…”

Section: Resultsmentioning

confidence: 54%

Hyaluronan Synthesis Is Inhibited by Adenosine Monophosphate-activated Protein Kinase through the Regulation of HAS2 Activity in Human Aortic Smooth Muscle Cells

Vigetti

Clerici

Deleonibus

et al. 2011

Journal of Biological Chemistry

106

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Hyaluronan (HA) is an extracellular matrix glycosaminoglycan (GAG) involved in cell motility, proliferation, tissue remodeling, development, differentiation, inflammation, tumor progression, and invasion and controls vessel thickening in cardiovascular diseases. Therefore, the control of HA synthesis could permit the finetuning of cell behavior, but the mechanisms that regulate HA synthesis are largely unknown. Recent studies suggest that the availability of the nucleotide-sugar precursors has a critical role. Because the formation of UDP-sugars is a highly energetically demanding process, we have analyzed whether the energy status of the cell could control GAG production. AMP-activated protein kinase (AMPK) is the main ATP/AMP sensor of mammalian cells, and we mimicked an energy stress by treating human aortic smooth muscle cells (AoSMCs) with the AMPK activators 5-aminoimidazole-4-carboxamide-1-␤-D-ribofuranoside and metformin. Under these conditions, HA synthesis, but not that of the other GAGs, was greatly reduced. We confirmed the inhibitory effect of AMPK using a specific inhibitor and knock-out cell lines. We found that AMPK phosphorylated Thr-110 of human HAS2, which inhibits its enzymatic activity. In contrast, the other two HAS isoenzymes (HAS1 and HAS3) were not modified by the kinase. The reduction of HA decreased the ability of AoSMCs to proliferate, migrate, and recruit immune cells, thereby reducing the pro-atherosclerotic AoSMC phenotype. Interestingly, such effects were not recovered by treatment with exogenous HA, suggesting that AMPK can block the pro-atherosclerotic signals driven by HA by interaction with its receptors.

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Section: Resultsmentioning

confidence: 54%

Hyaluronan Synthesis Is Inhibited by Adenosine Monophosphate-activated Protein Kinase through the Regulation of HAS2 Activity in Human Aortic Smooth Muscle Cells

Vigetti

Clerici

Deleonibus

et al. 2011

Journal of Biological Chemistry

106

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“…Accumulating evidence suggests that the effect of PPAR ligands to reduce 35 S-sulphate incorporation into CPC-precipitable material under low glucose conditions is concomitant with a reduction in GAG length on secreted proteoglycans (de Dios et al, 2007;Nigro et al, 2004;Tannock et al, 2004). To determine whether or not the effect of PPAR ligands to increase ( 3 H)-hexosamine incorporation into CPC-precipitable material under low glucose conditions is associated with an increase in the relative molecular mass of the secreted proteoglycans, we assessed the electrophoretic mobility of the secreted proteoglycans by SDS-PAGE.…”

Section: Resultsmentioning

confidence: 99%

“…Both the glitazones and fibrates have a range of actions on VSMCs including the inhibition of proliferation (de Dios et al, 2003;Nigro et al, 2002) and of proteoglycan synthesis (de Dios et al, 2007;Nigro et al, 2004) and these effects have been manifest as inhibition of the development of atherosclerosis in animal models (Calkin et al, 2005;Collins et al, 2001;Duez et al, 2002). Nevertheless in large clinical trials the agents have not had profoundly beneficial effects on reducing the incidence of cardiovascular disease (Dormandy et al, 2005;Home et al, 2005;Keech et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

“…Synthetic ligands are used as drugs for the treatment of metabolic disorders of hyperlipidemia (PPAR-a) and the insulin resistance of Type 2 diabetes (PPAR-g) and they have important direct actions on cells of the cardiovascular system (de Dios et al, 2007;Little et al, 2007b;Nigro et al, 2004) and see review (Plutzky, 2003). For agents which have been used clinically PPAR-a (fenofibrate) and PPAR-g ligands (troglitazone, rosiglitazone and pioglitazone) the apparent beneficial early results from cell and animal studies have not been fulfilled in large clinical trials (Dormandy et al, 2005;Home et al, 2005;Keech et al, 2005) and indeed the actions of thiazolidinedione or glitazone PPAR-g ligands has been highly controversial (Diamond et al, 2007;Nissen et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

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The effect of PPAR ligands to modulate glucose metabolism alters the incorporation of metabolic precursors into proteoglycans synthesized by human vascular smooth muscle cells

Nigro

Potter‐Perigo

Ivey

et al. 2008

Archives of Physiology and Biochemistry

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PPAR ligands are important effectors of energy metabolism and can modify proteoglycan synthesis by vascular smooth muscle cells (VSMCs). Describing the cell biology of these important clinical agents is important for understanding their full clinical potential, including toxicity. Troglitazone (10 mM) and fenofibrate (30 mM) treatment of VSMCs reduces ( 35 S)-sulphate incorporation into proteoglycans due to a reduction of glycosaminoglycan (GAG) chain length. Conversely, under physiological glucose conditions (5.5 mM), the same treatment increases ( 3 H)-glucosamine incorporation into GAGs. This apparent paradox is the consequence of an increase in the intracellular ( 3 H)-galactosamine specific activity from 48.2 + 3.2 mCi/ mmol to 90.7 + 11.0 mCi/ mmol (P 5 0.001) and 57.1 + 2.6 mCi/ mmol (P 5 0.05) when VSMCs were treated with troglitazone and fenofibrate, respectively. The increased specific activity observed with troglitazone (10 mM) treatment correlates with a two-fold increase in glucose consumption, while fenofibrate (50 mM) treatment showed a modest (14.6%) increase in glucose consumption. We conclude that the sole use of glucosamine precursors to assess GAG biosynthesis results in misleading conclusions when assessing the effect of PPAR ligands on VSMC proteoglycan biosynthesis.

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“…Furthermore, isolated (chemically cleaved) GAG chains from biglycan from growth factor treated cells as well as the small free GAG chains that arise in cells supplemented with exogenous β-D-xyloside also show enhanced binding to LDL compared to the respective entities from untreated cells [26]. Treatment of cells with many mechanistic antagonists and cardiovascular drugs blocks this response [27][28][29] and furthermore, treatment of ApoE -/-mice with antagonists such as imatinib blocks PDGF-stimulated GAG hyperelongation in vitro and blocks lipid deposition in the vessel wall of mice ex vivo and in vivo [30,31]. Other drugs such as the angiotensin receptor blocker, telmisartan, reduce biglycan expression and lipid deposition in ApoE -/-mice [32].…”

Section: Introductionmentioning

confidence: 99%

Aortic Smooth Muscle Cells from ApoE(-/-) Mice Secrete Biglycan with Hyperelongated Glycosaminoglycan Chains

Osman¹,

Getachew

Little

2013

Clin Exp Pharmacol

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Atherosclerosis is the major underlying process of cardiovascular disease. Atherosclerosis commences with an initial pre-inflammatory phase of the trapping and accumulation of lipids in the vessel wall and this is followed by an inflammatory response. The trapping of lipids occurs via binding to proteoglycans, specifically biglycan, with hyperelongated glycosaminoglycan (GAG) chains. Models have been developed to study the aetiology as well as the effectiveness of medical and experimental interventions in preventing atherosclerosis. ApoE is an apolipoprotein associated with removal of lipids from peripheral tissues. Disruption of the ApoE gene in C57BL/6 mice produces mice which are ApoE -/-(ApoE deficient) and show elevated plasma lipids and accelerated development of atherosclerosis which is exacerbated on a high fat diet. These mice are widely used in studies of atherosclerosis. We investigated the possibility that changes in the size of biglycan might participate in the development of atherosclerosis in ApoE -/-mice. We prepared Aortic Smooth Muscle Cell (ASMC) cultures by the digestion technique from ApoE-/-and ApoE +/+ mice and studied the size of biglycan secreted by both cell types. The biglycan secreted by ASMCs for ApoE -/-mice was larger than that from ApoE +/+ ASMCs. The difference was not eliminated by treatment of cells with a high concentration of Platelet Derived Growth Factor (PDGF) or by treatment with the PDGF antagonist, imatinib. The size difference was however observed in the small free GAG chains (xyloside GAGs) secreted in cells supplemented with exogenous xyloside as a cellular assay of GAG synthesizing capacity. This result suggests that there is a hyperactivity of the fundamental GAG synthesizing capacity in the ASMCs from ApoE -/-mice. These data suggest that hyperelongated biglycan might be contributing to lipid accumulation in ApoE -/-mice used in studies of atherosclerosis and that some of the medical interventions might have an action to reverse this hyperelongation response.

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Regulation of the atherogenic properties of vascular smooth muscle proteoglycans by oral anti-hyperglycemic agents

Cited by 32 publications

References 47 publications

Hyaluronan Synthesis Is Inhibited by Adenosine Monophosphate-activated Protein Kinase through the Regulation of HAS2 Activity in Human Aortic Smooth Muscle Cells

Hyaluronan Synthesis Is Inhibited by Adenosine Monophosphate-activated Protein Kinase through the Regulation of HAS2 Activity in Human Aortic Smooth Muscle Cells

The effect of PPAR ligands to modulate glucose metabolism alters the incorporation of metabolic precursors into proteoglycans synthesized by human vascular smooth muscle cells

Aortic Smooth Muscle Cells from ApoE(-/-) Mice Secrete Biglycan with Hyperelongated Glycosaminoglycan Chains

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