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Your search keyword '"Babaev, Vladimir R."' showing total 150 results
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150 results on '"Babaev, Vladimir R."'

5. Tie 1 attenuation reduces murine atheroasclerosis in a dose-dependent and shear stress-specific manner

Author

Woo, Kel Vin, Qu, Xianghu, Babaev, Vladimir R., Linton, MacRae F., Guzman, Raul J., Fazio, Sergio, and Baldwin, H. Scott

Subjects
Cholesterol -- Properties -- Health aspects -- Genetic aspects, Endothelium -- Properties -- Health aspects -- Genetic aspects, Atherosclerosis -- Prevention -- Genetic aspects, Health care industry
Abstract

Although the response of endothelial cells to the disturbed blood flowin the vicinity of atherosclerotic lesions is known to be distinct from that elicited by nonatherogenic laminar flow, the mechanisms involved are poorly understood. Our initial studies confirmed that expression of the endothelial receptor tyrosine kinase Tie1 was evident at regions of atherogenic flow in mature animals. We therefore hypothesized that Tie1 plays a role in the endothelial response to atherogenic shear stress. Consistent with this, we found that [Tie1.sup.+/-] mice bred to the apoE-deficient background displayed a 35% reduction in atherosclerosis relative to [Tie1.sup.+/+];[Apoe.sup.-/-] mice. Since deletion of Tie1 results in embryonic lethality secondary to vascular dysfunction, we used conditional and inducible mutagenesis to study the effect of endothelial-specific Tie1 attenuation on atherogenesis in [Apoe.sup.-/-] mice and found a dose-dependent decrease in atherosclerotic lesions. Analysis of primary aortic endothelial cells indicated that atheroprotective laminar flow decreased Tie1 expression in vitro. Attenuation of Tie1 was associated with an increase in eNOS expression and Tie2 phosphorylation. In addition, Tie1 attenuation increased IkBα expression while decreasing ICAM levels. In summary, we have found that shear stress conditions that modulate atherogenic events also regulate Tie1 expression. Therefore, Tie1 may play a novel proinflammatory role in atherosclerosis., Introduction Atherosclerotic lesions have a predilection for locales exposed to disturbed blood flow that can trigger inflammation and apoptosis (1-5). Disturbed flow is seen at the aortic sinus and at [...]

Published
2011
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6. Reducing endoplasmic reticulum stress through a macrophage lipid chaperone alleviates atherosclerosis

Author

Erbay, Ebru, Babaev, Vladimir R., Mayers, Jared R., Makowski, Liza, Charles, Khanichi N., Snitow, Melinda E., Fazio, Sergio, Wiest, Michelle M., Watkins, Steven M., Linton, MacRae F., and Hotamisligil, Gokhan S.

Subjects
Endoplasmic reticulum -- Physiological aspects -- Research -- Genetic aspects, Stress (Physiology) -- Research -- Genetic aspects -- Physiological aspects, Molecular chaperones -- Physiological aspects -- Research -- Genetic aspects, Atherosclerosis -- Care and treatment -- Genetic aspects -- Research, Biological sciences, Health
Abstract

Macrophages show endoplasmic reticulum (ER) stress when exposed to lipotoxic signals associated with atherosclerosis, although the pathophysiological importance and the underlying mechanisms of this phenomenon remain unknown. Here we show that mitigation of ER stress with a chemical chaperone results in marked protection against lipotoxic death in macrophages and prevents macrophage fatty acid-binding protein-4 (aP2) expression. Using genetic and chemical models, we show that aP2 is the predominant regulator of lipid-induced macrophage ER stress. The absence of lipid chaperones incites an increase in the production of phospholipids rich in monounsaturated fatty acids and bioactive lipids that render macrophages resistant to lipid-induced ER stress. Furthermore, the impact of aP2 on macrophage lipid metabolism and the ER stress response is mediated by upregulation of key lipogenic enzymes by the liver X receptor. Our results demonstrate the central role for lipid chaperones in regulating ER homeostasis in macrophages in atherosclerosis and show that ER responses can be modified, genetically or chemically, to protect the organism against the deleterious effects of hyperlipidemia., Organelle-mediated stress, particularly ER stress, has recently emerged as a major pathophysiological paradigm underlying chronic metabolic diseases (1-8). In conjunction with its central role in protein synthesis, folding and transportation, [...]

Published
2009
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8. Lack of macrophage fatty-acid-binding protein aP2 protects mice deficient in apolipoprotein E against atherosclerosis

Author

Makowski, Liza, Boord, Jeffrey B., Maeda, Kazuhisa, Babaev, Vladimir R., Uysal, K. Teoman, Morgan, Maureen A., Parker, Rex A., Suttles, Jill, Fazio, Sergio, Hotamisligil, Gokhan S., and Linton, MacRae F.

Abstract

The adipocyte fatty-acid-binding protein, aP2, has an important role in regulating systemic insulin resistance and lipid metabolism. Here we demonstrate that aP2 is also expressed in macrophages, has a significant role in their biological responses and contributes to the development of atherosclerosis. Apolipoprotein E (ApoE)-deficient mice also deficient for aP2 showed protection from atherosclerosis in the absence of significant differences in serum lipids or insulin sensitivity. aP2-deficient macrophages showed alterations in inflammatory cytokine production and a reduced ability to accumulate cholesterol esters when exposed to modified lipoproteins. Apoe[sup.-/-] mice with Ap2[sup.+/+] adipocytes and Ap2[sup.-/-] macrophages generated by bone-marrow transplantation showed a comparable reduction in atherosclerotic lesions to those with total aP2 deficiency, indicating an independent role for macrophage aP2 in atherogenesis. Through its distinct actions in adipocytes and macrophages, aP2 provides a link between features of the metabolic syndrome and could be a new therapeutic target for the prevention of atherosclerosis., Author(s): Liza Makowski [1, 7]; Jeffrey B. Boord [2, 7]; Kazuhisa Maeda [1]; Vladimir R. Babaev [2]; K. Teoman Uysal [1]; Maureen A. Morgan [5]; Rex A. Parker [5]; Jill [...]

Published
2001
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12. Loss of two Akt isoforms in hematopoietic cells diminished monocyte and macrophage survival and reduces atherosclerosis in Ldl-receptor null mice

Author

Babaev, Vladimir R., Ding, Lei, Zhang, Youmin, May, James M., Ramsey, Stephen A., Vickers, Kasey C., and Linton, MacRae F.

Subjects
Male, Cell Survival, Hematopoietic System, Macrophages, Atherosclerosis, Article, Monocytes, Mice, Inbred C57BL, Mice, Receptors, LDL, embryonic structures, Animals, Protein Isoforms, Female, Proto-Oncogene Proteins c-akt
Abstract

OBJECTIVE: Macrophages express three Akt isoforms, Akt1, Akt2 and Akt3, which display isoform-specific functions but may be redundant in terms of Akt survival signaling. We hypothesize that loss of two Akt isoforms in macrophages will suppress their ability to survive and modulate the development of atherosclerosis. APPROACH AND RESULTS: To test this hypothesis, we reconstituted male Ldl-receptor null (Ldlr(−/−)) mice with double Akt2/Akt3 knockout hematopoietic cells expressing only the Akt1 isoform (Akt1(only)). There were no differences in body weight and plasma lipid levels between the groups after 8 weeks of the Western diet, however Akt1(only)→Ldlr(−/−) mice developed smaller (57.6% reduction) atherosclerotic lesions with more apoptotic macrophages than control mice transplanted with wild-type (WT) cells. Next, male and female Ldlr(−/−) mice were reconstituted with double Akt1/Akt2 knockout hematopoietic cells expressing the Akt3 isoform (Akt3(only)). Female and male Akt3(only)→Ldlr(−/−) recipients had significantly smaller (61 and 41%, respectively) lesions than the control WT→Ldlr(−/−) mice. Loss of two Akt isoforms in hematopoietic cells resulted in markedly diminished levels of white blood cells, B-cells and monocytes, and compromised viability of monocytes and peritoneal macrophages compared to WT cells. In response to LPS, macrophages with a single Akt isoform expressed low levels of inflammatory cytokines, however Akt1(only) macrophages were distinct in expressing high levels of anti-apoptotic Il10 compared to WT and Akt3(only) cells. CONCLUSIONS: Loss of two Akt isoforms in hematopoietic cells, preserving only a single Akt1 or Akt3 isoform, markedly compromises monocyte and macrophage viability and diminishes early atherosclerosis in Ldlr(−/−)mice.

Published
2019

20. Identification of SPRR3 as a novel atheroprotective factor that promotes adaptive Akt signaling in VSMCs

Author

Segedy, Amanda K., Pyle, Amy L., Li, Bin, Zhang, Youmin, Babaev, Vladimir R., Jat, Parmjit, Fazio, Sergio, Atkinson, James B., Linton, MacRae F., and Young, Pampee P.

Subjects
Male, Mice, Knockout, Cell Survival, Macrophages, Myocytes, Smooth Muscle, Endothelial Cells, Apoptosis, Atherosclerosis, Adaptation, Physiological, Article, Plaque, Atherosclerotic, Mice, Inbred C57BL, Mice, Apolipoproteins E, Cornified Envelope Proline-Rich Proteins, Disease Progression, Animals, Female, Phosphorylation, Proto-Oncogene Proteins c-akt, Cell Proliferation, Signal Transduction
Abstract

Atherosclerosis is the primary driver of cardiovascular disease, the leading cause of death worldwide. Identification of naturally occurring atheroprotective genes has become a major goal for the development of interventions that will limit atheroma progression and associated adverse events. To this end, we have identified small proline-rich repeat protein (SPRR3) as selectively upregulated in vascular smooth muscle cells (VSMCs) of atheroma-bearing arterial tissue versus healthy arterial tissue. In this study, we sought to determine the role of SPRR3 in atheroma pathophysiology.We found that atheroprone apolipoprotein E-null mice lacking SPRR3 developed significantly greater atheroma burden. To determine the cellular driver(s) of this increase, we evaluated SPRR3-dependent changes in bone marrow-derived cells, endothelial cells, and VSMCs. Bone marrow transplant of SPRR3-expressing cells into SPRR3(-/-)apolipoprotein E-deficient recipients failed to rescue atheroma burden. Similarly, endothelial cells did not exhibit a response to SPRR3 loss. However, atheromas from SPRR3-deficient mice exhibited increased TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling)-positive VSMCs compared with control. Cell death in SPRR3-deficient VSMCs was significantly increased in vitro. Conversely, SPRR3-overexpressing VSMCs exhibited reduced apoptosis compared with control. We also observed a PI3K (phosphatidylinositol 3-kinase)/Akt-dependent positive association between SPRR3 expression and levels of active Akt in VSMCs. The survival advantage seen in SPRR3-overexpressing VSMCs was abrogated after the addition of a PI3K/Akt pathway inhibitor.These results indicate that SPRR3 protects the lesion from VSMC loss by promoting survival signaling in plaque VSMCs, thereby significantly decreasing atherosclerosis progression. As the first identified atheroma-specific VSMC prosurvival factor, SPRR3 represents a potential target for lesion-specific modulation of VSMC survival.

Published
2014

32. Macrophage Mal1 Deficiency Suppresses Atherosclerosis in Low-Density Lipoprotein Receptor–Null Mice by Activating Peroxisome Proliferator-Activated Receptor-γ–Regulated Genes

Author

Babaev, Vladimir R., primary, Runner, Robert P., additional, Fan, Daping, additional, Ding, Lei, additional, Zhang, Youmin, additional, Tao, Huan, additional, Erbay, Ebru, additional, Görgün, Cem Z., additional, Fazio, Sergio, additional, Hotamisligil, Gökhan S., additional, and Linton, MacRae F., additional

Published
2011
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33. Angiotensin type 1 receptor modulates macrophage polarization and renal injury in obesity

Author

Ma, Li-Jun, primary, Corsa, Bridgette A., additional, Zhou, Jun, additional, Yang, HaiChun, additional, Li, HaiJing, additional, Tang, Yi-Wei, additional, Babaev, Vladimir R., additional, Major, Amy S., additional, Linton, MacRae F., additional, Fazio, Sergio, additional, Hunley, Tracy E., additional, Kon, Valentina, additional, and Fogo, Agnes B., additional

Published
2011
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42. Angiotensin II Amplifies Macrophage-Driven Atherosclerosis

Author

Nobuhiko, Ayabe, primary, Suganuma, Eisuke, additional, Babaev, Vladimir R., additional, Fogo, Agnes, additional, Swift, Larry L., additional, Linton, MacRae F., additional, Fazio, Sergio, additional, Ichikawa, Iekuni, additional, and Kon, Valentina, additional

Published
2004
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