Person: Zheng, Carson
Loading...
Email Address
AA Acceptance Date
Birth Date
Research Projects
Organizational Units
Job Title
Last Name
Zheng
First Name
Carson
Name
Zheng, Carson
5 results
Search Results
Now showing 1 - 5 of 5
Publication Deletion of EP4 on Bone Marrow-Derived Cells Enhances Inflammation and Angiotensin II-Induced Abdominal Aortic Aneurysm Formation(Ovid Technologies (Wolters Kluwer Health), 2010) Tang, E. H. C.; Shvartz, E.; Shimizu, K.; Rocha, V. Z.; Zheng, Carson; Fukuda, D.; Shi, Guo-Ping; Sukhova, Galina; Libby, PeterObjective—To examine whether a lack of prostaglandin E receptor 4 (EP4) on bone marrow–derived cells would increase local inflammation and enhance the formation of abdominal aortic aneurysm (AAA) in vivo. Methods and Results—Prostaglandin E2 (PGE2) through activation of EP4, can mute inflammation. Hypercholesterolemic low-density lipoprotein receptor knockout (LDLR−/−) mice transplanted with either EP4+/+ (EP4+/+/LDLR−/−) or EP4−/− (EP4−/−/LDLR−/−) bone marrow received infusions of angiotensin II to induce AAA. Deficiency of EP4 on bone marrow–derived cells increased the incidence (50% of male EP4+/+/LDLR−/− mice versus 88.9% of male EP4−/−/LDLR−/− mice developed AAA; and 22% of female EP4+/+/LDLR−/− mice versus 83.3% of female EP4−/−/LDLR−/− mice developed AAA) and severity of AAA, increased monocyte chemoattractant protein-1 (2.72-fold in males and 1.64-fold in females), and enhanced infiltration of macrophages (3.8-fold in males and 2.44-fold in females) and T cells (1.88-fold in males and 1.66-fold in females) into AAA lesions. Lack of EP4 on bone marrow–derived cells augmented elastin fragmentation, increased apoptotic markers, and decreased smooth muscle cell accumulation within AAA lesions. Conclusion—Deficiency of EP4 on bone marrow–derived cells boosted inflammation and AAA formation induced by angiotensin II in hyperlipidemic mice. This study affirms the pathophysiologic importance of PGE2 signaling through EP4 as an endogenous anti-inflammatory pathway involved in experimental aneurysm formation.Publication Apolipoprotein C-III and the Metabolic Basis for Hypertriglyceridemia and the Dense Low-Density Lipoprotein Phenotype(Ovid Technologies (Wolters Kluwer Health), 2010) Zheng, Carson; Khoo, C.; Furtado, J.; Sacks, FrankBACKGROUND: Here, we aim to identify defects of apolipoprotein (apo) B lipoprotein metabolism that characterize hypertriglyceridemia, focusing on apoC-III and apoE. METHODS AND RESULTS: We studied the transport of plasma apoB within 21 distinct subfractions as separated by anti-apoC-III and anti-apoE immunoaffinity chromatography and ultracentrifugation in 9 patients with moderate hypertriglyceridemia and 12 normotriglyceridemic control subjects. Hypertriglyceridemia was characterized by a 3-fold higher liver secretion of very low-density lipoprotein (VLDL) that had apoC-III but not apoE and a 50% lower secretion of VLDL with both apoC-III and apoE (both P<0.05). This shift in VLDL secretion pattern from apoE to apoC-III resulted in significantly reduced clearance of light VLDL (-39%; P<0.05), compatible with the antagonizing effects of apoC-III on apoE-induced clearance of triglyceride-rich lipoproteins. In addition, rate constants for clearance were reduced for apoE-containing triglyceride-rich lipoproteins in hypertriglyceridemia, associated with increased apoC-III contents of these particles. LDL distribution shifted from light and medium LDL to dense LDL in hypertriglyceridemia through a quartet of kinetic perturbations: increased flux from apoC-III-containing triglyceride-rich lipoproteins, a shift in liver LDL secretion pattern from light to dense LDL, an increased conversion rate from light and medium LDL to dense LDL, and retarded catabolism of dense LDL. CONCLUSIONS: These results support a central role for apoC-III in metabolic defects leading to hypertriglyceridemia. Triglyceride-rich lipoprotein metabolism shifts from an apoE-dominated system in normotriglyceridemic participants characterized by rapid clearance from circulation of VLDL to an apoC-III-dominated system in hypertriglyceridemic patients characterized by reduced clearance of triglyceride-rich lipoproteins and the formation of the dense LDL phenotype.Publication Selective delipidation of plasma HDL enhances reverse cholesterol transport in vivo(American Society for Biochemistry & Molecular Biology (ASBMB), 2008) Sacks, Frank; Rudel, L. L.; Conner, A.; Akeefe, H.; Kostner, G.; Baki, T.; Rothblat, G.; de la Llera-Moya, M.; Asztalos, B.; Perlman, T.; Zheng, Carson; Alaupovic, P.; Maltais, J.-A. B.; Brewer, H. B.Uptake of cholesterol from peripheral cells by nascent small HDL circulating in plasma is necessary to prevent atherosclerosis. This process, termed reverse cholesterol transport, produces larger cholesterol-rich HDL that transfers its cholesterol to the liver facilitating excretion. Most HDL in plasma is cholesterol-rich. We demonstrate that treating plasma with a novel selective delipidation procedure converts large to small HDL [HDL-selectively delipidated (HDL-sdl)]. HDL-sdl contains several cholesterol-depleted species resembling small alpha, prebeta-1, and other prebeta forms. Selective delipidation markedly increases efficacy of plasma to stimulate ABCA1-mediated cholesterol transfer from monocytic cells to HDL. Plasma from African Green monkeys underwent selective HDL delipidation. The delipidated plasma was reinfused into five monkeys. Prebeta-1-like HDL had a plasma residence time of 8 +/- 6 h and was converted entirely to large alpha-HDL having residence times of 13-14 h. Small alpha-HDL was converted entirely to large alpha-HDL. These findings suggest that selective HDL delipidation activates reverse cholesterol transport, in vivo and in vitro. Treatment with delipidated plasma tended to reduce diet-induced aortic atherosclerosis in monkeys measured by intravascular ultrasound. These findings link the conversion of small to large HDL, in vivo, to improvement in atherosclerosis.Publication Rapid turnover of apolipoprotein C-III-containing triglyceride-rich lipoproteins contributing to the formation of LDL subfractions(American Society for Biochemistry & Molecular Biology (ASBMB), 2007) Zheng, Carson; Khoo, C.; Ikewaki, K.; Sacks, FrankThe atherogenicity theory for triglyceride-rich lipoproteins (TRLs; VLDL + intermediate density lipoprotein) generally cites the action of apolipoprotein C-III (apoC-III), a component of some TRLs, to retard their metabolism in plasma. We studied the kinetics of multiple TRL and LDL subfractions according to the content of apoC-III and apoE in 11 hypertriglyceridemic and normolipidemic persons. The liver secretes mainly two types of apoB lipoproteins: TRL with apoC-III and LDL without apoC-III. Approximately 45% of TRLs with apoC-III are secreted together with apoE. Contrary to expectation, TRLs with apoC-III but not apoE have fast catabolism, losing some or all of their apoC-III and becoming LDL. In contrast, apoE directs TRL flux toward rapid clearance, limiting LDL formation. Direct clearance of TRL with apoC-III is suppressed among particles also containing apoE. TRLs without apoC-III or apoE are a minor, slow-metabolizing precursor of LDL with little direct removal. Increased VLDL apoC-III levels are correlated with increased VLDL production rather than with slow particle turnover. Finally, hypertriglyceridemic subjects have significantly greater production of apoC-III-containing VLDL and global prolongation in residence time of all particle types. ApoE may be the key determinant of the metabolic fate of atherogenic apoC-III-containing TRLs in plasma, channeling them toward removal from the circulation and reducing the formation of LDLs, both those with apoC-III and the main type without apoC-III.Publication Statins Suppress Apolipoprotein CIII-Induced Vascular Endothelial Cell Activation and Monocyte Adhesion(Oxford University Press, 2012) Zheng, Carson; Azcutia, Veronica; Aikawa, Elena; Figueiredo, Jose-Luiz; Croce, Kevin; Sonoki, Hiroyuki; Sacks, Frank; Luscinskas, Francis; Aikawa, MasanoriAims: Activation of vascular endothelial cells (ECs) contributes importantly to inflammation and atherogenesis. We previously reported that apolipoprotein CIII (apoCIII), found abundantly on circulating triglyceride-rich lipoproteins, enhances adhesion of human monocytes to ECs in vitro. Statins may exert lipid-independent anti-inflammatory effects. The present study examined whether statins suppress apoCIII-induced EC activation in vitro and in vivo. Methods and results: Physiologically relevant concentrations of purified human apoCIII enhanced attachment of the monocyte-like cell line THP-1 to human saphenous vein ECs (HSVECs) or human coronary artery ECs (HCAECs) under both static and laminar shear stress conditions. This process mainly depends on vascular cell adhesion molecule-1 (VCAM-1), as a blocking VCAM-1 antibody abolished apoCIII-induced monocyte adhesion. ApoCIII significantly increased VCAM-1 expression in HSVECs and HCAECs. Pre-treatment with statins suppressed apoCIII-induced VCAM-1 expression and monocyte adhesion, with two lipophilic statins (pitavastatin and atorvastatin) exhibiting inhibitory effects at lower concentration than those of hydrophilic pravastatin. Nuclear factor κB (NF-κB) mediated apoCIII-induced VCAM-1 expression, as demonstrated via loss-of-function experiments, and pitavastatin treatment suppressed NF-κB activation. Furthermore, in the aorta of hypercholesterolaemic \(Ldlr^{−/−}\) mice, pitavastatin administration in vivo suppressed VCAM-1 mRNA and protein, induced by apoCIII bolus injection. Similarly, in a subcutaneous dorsal air pouch mouse model of leucocyte recruitment, apoCIII injection induced F4/80+ monocyte and macrophage accumulation, whereas pitavastatin administration reduced this effect. Conclusions: These findings further establish the direct role of apoCIII in atherogenesis and suggest that anti-inflammatory effects of statins could improve vascular disease in the population with elevated plasma apoCIII.