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Sukhova, Galina

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Sukhova

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Galina

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Sukhova, Galina
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    Local proliferation dominates lesional macrophage accumulation in atherosclerosis
    (2013) Robbins, Clinton S.; Hilgendorf, Ingo; Weber, Georg F.; Theurl, Igor; Iwamoto, Yoshiko; Figueiredo, Jose-Luiz; Gorbatov, Rostic; Sukhova, Galina; Gerhardt, Louisa M.S.; Smyth, David; Zavitz, Caleb C. J.; Shikatani, Eric A.; Parsons, Michael; van Rooijen, Nico; Lin, Herbert; Husain, Mansoor; Libby, Peter; Nahrendorf, Matthias; Weissleder, Ralph; Swirski, Filip
    During the inflammatory response that drives atherogenesis, macrophages accumulate progressively in the expanding arterial wall1,2. The observation that circulating monocytes give rise to lesional macrophages3–9 has reinforced the concept that monocyte infiltration dictates macrophage build-up. Recent work indicates, however, that macrophages do not depend on monocytes in some inflammatory contexts10. We therefore revisited the mechanism of macrophage accumulation in atherosclerosis. We show that murine atherosclerotic lesions experience a surprisingly rapid, 4-week, cell turnover. Replenishment of macrophages in these experimental atheromata depends predominantly on local macrophage proliferation rather than monocyte influx. The microenvironment orchestrates macrophage proliferation via the involvement of scavenger receptor (SR)-A. Our study reveals macrophage proliferation as a key event in atherosclerosis and identifies macrophage self-renewal as a therapeutic target for cardiovascular disease.
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    Cystatin C deficiency in human atherosclerosis and aortic aneurysms
    (American Society for Clinical Investigation, 1999) Shi, Guo-Ping; Sukhova, Galina; Grubb, Anders; Ducharme, Anique; Rhode, Luis H.; Lee, Richard; Ridker, Paul; Libby, Peter; Chapman, Harold A.
    The pathogenesis of atherosclerosis and abdominal aortic aneurysm involves breakdown of the elastic laminae. Elastolytic cysteine proteases, including cathepsins S and K, are overexpressed at sites of arterial elastin damage, but whether endogenous local inhibitors counterbalance these proteases is unknown. We show here that, whereas cystatin C is normally expressed in vascular wall smooth muscle cells (SMCs), this cysteine protease inhibitor is severely reduced in both atherosclerotic and aneurysmal aortic lesions. Furthermore, increased abdominal aortic diameter among 122 patients screened by ultrasonography correlated inversely with serum cystatin C levels. In vitro, cytokine-stimulated vascular SMCs secrete cathepsins, whose elastolytic activity could be blocked when cystatin C secretion was induced by treatment with TGF-β1. The findings highlight a potentially important role for imbalance between cysteine proteases and cystatin C in arterial wall remodeling and establish that cystatin C deficiency occurs in vascular disease.
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    Selective Inhibition of Matrix Metalloproteinase-13 Increases Collagen Content of Established Mouse Atherosclerosis
    (Ovid Technologies (Wolters Kluwer Health), 2011) Quillard, T.; Tesmenitsky, Y.; Croce, Kevin; Travers, R.; Shvartz, E.; Koskinas, K. C.; Sukhova, Galina; Aikawa, Elena; Aikawa, Masanori; Libby, Peter
    Objective—Evidence has linked collagen loss with the onset of acute coronary events. This study tested the hypothesis that selective matrix metalloproteinase-13 (MMP-13) collagenase inhibition increases collagen content in already established and nascent mouse atheromas. Methods and Results—In vitro and in situ experiments documented the selectivity and efficacy of an orally available MMP-13 inhibitor (MMP13i-A). In vivo observations monitored macrophage accumulation and MMP-13 activity using molecular imaging. After 10 weeks of MMP13i-A treatment, apolipoprotein E–deficient mice with evolving or established lesions exhibited reduced MMP-13 activity without affecting macrophage content, measured either by intravital microscopy or fluorescence reflectance imaging. Histological analysis indicated that MMP13-iA did not affect plaque size or macrophage or smooth muscle cell accumulation. Administration of MMP13i-A to mice with evolving or established atheromas substantially increased plaque interstitial collagen content in the intima and locally in the fibrous cap, compared with vehicle-treated controls. Analysis of collagen revealed thicker collagen fibers within the plaques of treated groups. Conclusion—Pharmacological MMP-13 inhibition yields collagen accumulation in plaques (a feature associated in humans with resistance to rupture), even in established plaques. This study, of considerable clinical relevance, furnishes new mechanistic insight into regulation of the plaque's extracellular matrix and validates molecular imaging for studying plaque biology.
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    CXCR3 Controls T-Cell Accumulation in Fat Inflammation
    (Ovid Technologies (Wolters Kluwer Health), 2014) Rocha, V. Z.; Folco, Eduardo; Ozdemir, Cafer; Sheikine, Y.; Christen, T.; Sukhova, Galina; Tang, E. H. C.; Bittencourt, M. S.; Santos, R. D.; Luster, Andrew; Cohen, David E.; Libby, Peter
    Objective—Obesity associates with increased numbers of inflammatory cells in adipose tissue (AT), including T cells, but the mechanism of T-cell recruitment remains unknown. This study tested the hypothesis that the chemokine receptor CXCR3 participates in T-cell accumulation in AT of obese mice and thus in the regulation of local inflammation and systemic metabolism. Approach and Results—Obese wild-type mice exhibited higher mRNA expression of CXCR3 in periepididymal AT-derived stromal vascular cells compared with lean mice. We evaluated the function of CXCR3 in AT inflammation in vivo using CXCR3-deficient and wild-type control mice that consumed a high-fat diet. Periepididymal AT from obese CXCR3-deficient mice contained fewer T cells than obese controls after 8 and 16 weeks on high-fat diet, as assessed by flow cytometry. Obese CXCR3-deficient mice had greater glucose tolerance than obese controls after 8 weeks, but not after 16 weeks. CXCR3-deficient mice fed high-fat diet had reduced mRNA expression of proinflammatory mediators, such as monocyte chemoattractant protein-1 and regulated on activation, normal T cell expressed and secreted, and anti-inflammatory genes, such as Foxp3, IL-10, and arginase-1 in periepididymal AT, compared with obese controls. Conclusions—These results demonstrate that CXCR3 contributes to T-cell accumulation in periepididymal AT of obese mice. Our results also suggest that CXCR3 regulates the accumulation of distinct subsets of T cells and that the ratio between these functional subsets across time likely modulates local inflammation and systemic metabolism.
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    Cathepsin L Activity Is Essential to Elastase Perfusion-Induced Abdominal Aortic Aneurysms in Mice
    (Ovid Technologies (Wolters Kluwer Health), 2011) Sun, Jiusong; Sukhova, Galina; Zhang, Jie; Chen, Han; Sjoberg, S.; Libby, Peter; Xiang, M.; Wang, J.; Peters, C.; Reinheckel, T.; Shi, Guo-Ping
    Objective—The development of abdominal aortic aneurysms (AAA) requires extensive aortic wall matrix degradation. Human AAA lesions express high levels of cathepsin L (CatL), one of the most potent mammalian elastases. Whether this protease participates directly in AAA pathogenesis, however, is unknown. Methods and Results—We generated experimental AAA with aortic elastase perfusion in mice and established an essential role of CatL in AAA formation. After 14 days postperfusion, most wild-type (Ctsl+/+) mice developed AAA, but none of the CatL-deficient (Ctsl−/−) mice did. AAA lesion macrophage contents, CD4+ T cell numbers, CD31+ and laminin-5 angiogenic fragment γ2+ microvessel numbers, and elastin fragmentation were all significantly lower in Ctsl−/− mice than in Ctsl+/+ mice. While lesions from Ctsl−/− mice contained fewer Ki67+ proliferating cells than did Ctsl+/+ mice, the absence of CatL did not affect lesion apoptotic cell contents or medial smooth-muscle cell loss significantly. Mechanistic studies indicated that the absence of CatL reduced lesion chemokine monocyte chemotactic protein-1 content, macrophage and T-cell in vitro transmigration, and angiogenesis, and altered the expression and activities of matrix metalloproteinases and other cysteinyl cathepsins in inflammatory cells, vascular cells, and AAA lesions. Conclusion—CatL contributes to AAA formation by promoting lesion inflammatory cell accumulation, angiogenesis, and protease expression.
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    Lack of EP4 receptors on bone marrow-derived cells enhances inflammation in atherosclerotic lesions
    (Oxford University Press (OUP), 2010) Tang, E. H. C.; Shimizu, K.; Christen, T.; Rocha, V. Z.; Shvartz, E.; Tesmenitsky, Y.; Sukhova, Galina; Shi, Guo-Ping; Libby, Peter
    Aim: Prostaglandin E2, by ligation of its receptor EP4, suppresses the production of inflammatory cytokines and chemokines in macrophages in vitro. Thus, activation of EP4 may constitute an endogenous anti-inflammatory pathway. This study investigated the role of EP4 in atherosclerosis in vivo, and particularly its impact on inflammation. Methods and results: Ldlr−/− mice transplanted with EP4+/+ or EP4−/− bone marrow consumed a high-fat diet for 5 or 10 weeks. Allogenic bone marrow transplantation promoted exacerbation of atherosclerosis irrespective of EP4 genotype, compatible with prior observations of exacerbated atherogenesis by allogenicity. EP4 deficiency had little effect on plaque size or morphology in early atherosclerosis, but at the later time point, mice deficient in EP4 displayed enhanced inflammation in their atherosclerotic plaques. Expression of monocyte chemoattractant protein-1 and interferon-γ inducible protein 10 increased, and there was a corresponding increase in macrophage and T-cell infiltration. These plaques also contained fewer smooth muscle cells. Despite these changes, mice deficient in EP4 in bone marrow-derived cells at an advanced stage had similar lesion size (in both aorta and aortic root) as mice with EP4. Conclusion: This study shows that in advanced atherosclerosis, EP4 deficiency did not alter atherosclerotic lesion size, but yielded plaques with exacerbated inflammation and altered lesion composition.
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    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, Peter
    Objective—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.
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    Echocardiography-derived left ventricular end-systolic regional wall stress and matrix remodeling after experimental myocardial infarction
    (Elsevier BV, 1999) Rohde, Luis E; Aikawa, Masanori; Cheng, George Z; Sukhova, Galina; Solomon, Scott; Libby, Peter; Pfeffer, Janice; Pfeffer, Marc; Lee, Richard
    OBJECTIVES We tested the hypothesis that regional end-systolic left ventricular (ESLV) wall stress is associated with extracellular matrix remodeling activity after myocardial infarction (MI). BACKGROUND Increased left ventricular (LV) wall stress is a stimulus for LV enlargement, and echocardiography can be used to estimate regional wall stress. A powerful validation of a noninvasive method of estimating wall stress would be predicting cellular responses after a MI. METHODS Echocardiographic images were obtained in rats 1, 7, 14 or 21 days after coronary ligation (n = 11) or sham surgery (n = 5). End-systolic left ventricular wall stress was calculated by finite element analysis in three regions (infarcted, noninfarcted and border) from short-axis images. Matrix metalloproteinase-9 (MMP-9) and macrophage density were determined by immunohistochemistry, and positive cells were counted in high power fields (hpf). RESULTS Average ESLV wall stress was higher in rats with MI when compared to shams irrespective of time point (p < 0.01), and ESLV wall stress in the infarcted regions increased with time (25.1 ± 5.9 vs. 69.9 ± 4.4 kdyn/cm2, day 1 vs. 21; p < 0.01). Matrix metalloproteinase-9 expression was higher in infarcted and border regions when compared to noninfarcted regions (22.1 vs. 25.7 vs. 0.10 cells/hpf, respectively; p < 0.01). Over all regions, ESLV wall stress was associated with MMP-9 (r = 0.76; p < 0.001), macrophage density (r = 0.72; p < 0.001) and collagen content (r = 0.67; p < 0.001). End-systolic left ventricular wall stress was significantly higher when MMP-9 positive cell density was greater than 10 cells/hpf (45 ± 20 vs. 14 ± 10 kdyn/cm2; p < 0.001). CONCLUSIONS Regional increases in ESLV wall stress determined by echocardiography-based structural analysis are associated with extracellular matrix degradation activity.
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    Mast cells modulate the pathogenesis of elastase-induced abdominal aortic aneurysms in mice
    (American Society for Clinical Investigation, 2007) Sun, Jiusong; Sukhova, Galina; Yang, Min; Wolters, Paul J.; MacFarlane, Lindsey; Libby, Peter; Sun, Chongxiu; Zhang, Yadong; Liu, Jianming; Ennis, Terri L.; Knispel, Rebecca; Xiong, Wanfen; Thompson, Robert W.; Baxter, B. Timothy; Shi, Guo-Ping
    Abdominal aortic aneurysm (AAA), an inflammatory disease, involves leukocyte recruitment, immune responses, inflammatory cytokine production, vascular remodeling, neovascularization, and vascular cell apoptosis, all of which contribute to aortic dilatation. This study demonstrates that mast cells, key participants in human allergic immunity, participate in AAA pathogenesis in mice. Mast cells were found to accumulate in murine AAA lesions. Mast cell–deficient KitW-sh/KitW-sh mice failed to develop AAA elicited by elastase perfusion or periaortic chemical injury. KitW-sh/KitW-sh mice had reduced aortic expansion and internal elastic lamina degradation; decreased numbers of macrophages, CD3+ T lymphocytes, SMCs, apoptotic cells, and CD31+ microvessels; and decreased levels of aortic tissue IL-6 and IFN-γ. Activation of mast cells in WT mice via C48/80 injection resulted in enhanced AAA growth while mast cell stabilization with disodium cromoglycate diminished AAA formation. Mechanistic studies demonstrated that mast cells participated in angiogenesis, aortic SMC apoptosis, and matrix-degrading protease expression. Reconstitution of KitW-sh/KitW-sh mice with bone marrow–derived mast cells from WT or TNF-α–/– mice, but not from IL-6–/– or IFN-γ–/– mice, caused susceptibility to AAA formation to be regained. These results demonstrate that mast cells participate in AAA pathogenesis in mice by releasing proinflammatory cytokines IL-6 and IFN-γ, which may induce aortic SMC apoptosis, matrix-degrading protease expression, and vascular wall remodeling, important hallmarks of arterial aneurysms.
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    Deficiency of cathepsin S reduces atherosclerosis in LDL receptor–deficient mice
    (American Society for Clinical Investigation, 2003) Sukhova, Galina; Zhang, Yaou; Pan, Jie-Hong; Wada, Youichiro; Yamamoto, Takashi; Naito, Makoto; Kodama, Tatsuhiko; Tsimikas, Sotirios; Witztum, Joseph L.; Lu, Michael L.; Sakara, Yasuhiko; Chin, Michael T.; Libby, Peter; Shi, Guo-Ping
    Human atherosclerotic lesions overexpress the lysosomal cysteine protease cathepsin S (Cat S), one of the most potent mammalian elastases known. In contrast, atheromata have low levels of the endogenous Cat S inhibitor cystatin C compared with normal arteries, suggesting involvement of this protease in atherogenesis. The present study tested this hypothesis directly by crossing Cat S–deficient (CatS–/–) mice with LDL receptor–deficient (LDLR–/–) mice that develop atherosclerosis on a high-cholesterol diet. Compared with LDLR–/– mice, double-knockout mice (CatS–/–LDLR–/–) developed significantly less atherosclerosis, as indicated by plaque size (plaque area and intimal thickening) and stage of development. These mice also had markedly reduced content of intimal macrophages, lipids, smooth muscle cells, collagen, CD4+ T lymphocytes, and levels of IFN-γ. CatS–/–LDLR–/– monocytes showed impaired subendothelial basement membrane transmigration, and aortas from CatS–/–LDLR–/– mice had preserved elastic laminae. These findings establish a pivotal role for Cat S in atherogenesis.