Willa A Hsueh

Publications (67)476.26 Total impact

• Article: Nuclear Factor (Erythroid-Derived 2)-Like-2 Factor (Nrf2), a Key Regulator of the Antioxidant Response to Protect Against Atherosclerosis and Nonalcoholic Steatohepatitis.

  Anisha A Gupte, Christopher J Lyon, Willa A Hsueh
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  ABSTRACT: Tissue oxidative stress is a common hallmark of atherosclerosis and non-alcoholic steatohepatitis (NASH), 2 conditions linked epidemiologically and pathophysiologically. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is the master regulator of inducible antioxidant responses, that can attenuate cellular injury from oxidative stress induced by obesity and other redox insults. Nrf2 expression and activation is reduced in mouse and human vessels that harbor accelerated atherosclerosis and in livers with histologic criteria of NASH. Systemic antioxidants have thus been attractive therapeutic targets, but clinical trials have been largely unsuccessful in improving cardiovascular health. Macrophage-selective Nrf2 activation may, however, provide an approach to reduce vascular and hepatocyte injury without the complications of systemic antioxidants, since macrophages play key roles in the development and progression of both atherosclerosis and NASH. In this article, we review the common mechanisms of oxidative stress and inflammation in atherosclerosis and NASH, and discuss the role of Nrf2 in vascular and hepatocyte protection.
  Current Diabetes Reports 03/2013; · 2.50 Impact Factor
• Article: Class II Major Histocompatibility Complex Plays an Essential Role in Obesity-Induced Adipose Inflammation.

  Tuo Deng, Christopher J Lyon, Laurie J Minze, Jianxin Lin, Jia Zou, Joey Z Liu, Yuelan Ren, Zheng Yin, Dale J Hamilton, Patrick R Reardon, Vadim Sherman, Helen Y Wang, Kevin J Phillips, Paul Webb, Stephen T C Wong, Rong-Fu Wang, Willa A Hsueh
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  ABSTRACT: Adipose-resident T cells (ARTs) regulate metabolic and inflammatory responses in obesity, but ART activation signals are poorly understood. Here, we describe class II major histocompatibility complex (MHCII) as an important component of high-fat-diet (HFD)-induced obesity. Microarray analysis of primary adipocytes revealed that multiple genes involved in MHCII antigen processing and presentation increased in obese women. In mice, adipocyte MHCII increased within 2 weeks on HFD, paralleling increases in proinflammatory ART markers and decreases in anti-inflammatory ART markers, and preceding adipose tissue macrophage (ATM) accumulation and proinflammatory M1 polarization. Mouse 3T3-L1 and primary adipocytes activated T cells in an antigen-specific, contact-dependent manner, indicating that adipocyte MHCII is functional. HFD-fed MHCII mice developed less adipose inflammation and insulin resistance than did wild-type mice, despite developing similar adiposity. These investigations uncover a mechanism whereby a HFD-induced adipocyte/ART dialog involving MHCII instigates adipose inflammation and, together with ATM MHCII, escalates its progression.
  Cell metabolism 03/2013; 17(3):411-22. · 17.35 Impact Factor
• Article: Myeloid Deletion of Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2) Increases Atherosclerosis and Liver Injury.

  Alan R Collins, Anisha A Gupte, Ruirui Ji, Maricela R Ramirez, Laurie J Minze, Joey Z Liu, Magda Arredondo, Yuelan Ren, Tuo Deng, Jun Wang, Christopher J Lyon, Willa A Hsueh
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  ABSTRACT: OBJECTIVE: To determine the impact of hematopoietic deletion of nuclear factor- (erythroid-derived 2) like 2 factor (Nrf2) on the development of atherosclerosis and liver injury in an obese, hypercholesterolemic mouse model. METHODS AND RESULTS: Two-month-old male low-density lipoprotein receptor-deficient mice were lethally irradiated and transplanted with either wild type or Nrf2-deficient (Nrf2(-/-)) bone marrow cells. At 3 months of age, mice were placed on an obesogenic high-fat diet (HFD), high-cholesterol diet for 7 months. Despite no differences in body weight, body fat percentage, liver fat, plasma glucose, lipids, or insulin, the HFD-fed Nrf2(-/-) bone marrow recipients had increased proinflammatory vascular gene expression, a significant increase in atherosclerosis area (18% versus 28%; P=0.018) and lesion complexity, and a marked increase in liver fibrosis. The acceleration of vascular and liver injury may arise from enhanced macrophage migration, inflammation, and oxidative stress resulting from myeloid Nrf2 deficiency. CONCLUSIONS: Myeloid-derived Nrf2 activity attenuates atherosclerosis development and liver inflammation and fibrosis associated with obesity. Prevention of oxidative stress in macrophage and other myeloid lineage cells may be an important therapeutic target to reduce inflammation-driven complications of obesity.
  Arteriosclerosis Thrombosis and Vascular Biology 09/2012; · 6.37 Impact Factor
• Article: PGC-1α: the missing ingredient for mesenchymal stem cell-mediated angiogenesis.

  Willa A Hsueh, Anisha A Gupte
  Diabetes 05/2012; 61(5):979-80. · 8.29 Impact Factor
• Article: A Peroxisome Proliferator-activated Receptor γ (PPARγ)/PPARγ Coactivator 1β Autoregulatory Loop in Adipocyte Mitochondrial Function

  Tuo Deng, Douglas H. Sieglaff, Aijun Zhang, Christopher J. Lyon, Steven D. Ayers, Aleksandra Cvoro, Anisha A. Gupte, Xuefeng Xia, John D. Baxter, Paul Webb, Willa A. Hsueh
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  ABSTRACT: Peroxisome proliferator-activated receptor γ (PPARγ) activation induces adipogenesis and also enhances lipogenesis, mitochondrial activity, and insulin sensitivity in adipocytes. Whereas some studies implicate PPARγ coactivator 1α (PGC-1α) in the mitochondrial effect, the mechanisms involved in PPARγ regulation of adipocyte mitochondrial function are not resolved. PPARγ-activating ligands (thiazolidinediones (TZDs)) are important insulin sensitizers and were recently shown to indirectly induce PGC-1β transcription in osteoclasts. Here, we asked whether similar effects occur in adipocytes and show that TZDs also strongly induce PGC-1β in cultured 3T3-L1 cells. This effect, however, differs from the indirect effect proposed for bone and is rapid and direct and involves PPARγ interactions with an intronic PPARγ response element cluster in the PGC-1β locus. TZD treatment of cultured adipocytes results in up-regulation of mitochondrial marker genes, and increased mitochondrial activity and use of short interfering RNA confirms that these effects require PGC-1β. PGC-1β did not participate in PPARγ effects on adipogenesis or lipogenesis, and PGC-1β knockdown did not alter insulin-responsive glucose uptake into 3T3-L1 cells. Similar effects on PGC-1β and mitochondrial gene expression are seen in vivo; fractionation of obese mouse adipose tissue reveals that PPARγ and PGC-1β, but not PGC-1α, are coordinately up-regulated in adipocytes relative to preadipocytes and that TZD treatment induces PGC-1β and mitochondrial marker genes in adipose tissue of obese mice. We propose that PPARγ directly induces PGC-1β expression in adipocytes and that this effect regulates adipocyte mitochondrial activity.
  Journal of Biological Chemistry 09/2011; 286(35):30723-30731. · 4.77 Impact Factor
• Article: A peroxisome proliferator-activated receptor gamma (PPARgamma)/PPARgamma coactivator 1beta autoregulatory loop in adipocyte mitochondrial function.

  Tuo Deng, Douglas H Sieglaff, Aijun Zhang, Christopher J Lyon, Steven D Ayers, Aleksandra Cvoro, Anisha A Gupte, Xuefeng Xia, John D Baxter, Paul Webb, Willa A Hsueh
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  ABSTRACT: Peroxisome proliferator-activated receptor γ (PPARγ) activation induces adipogenesis and also enhances lipogenesis, mitochondrial activity, and insulin sensitivity in adipocytes. Whereas some studies implicate PPARγ coactivator 1α (PGC-1α) in the mitochondrial effect, the mechanisms involved in PPARγ regulation of adipocyte mitochondrial function are not resolved. PPARγ-activating ligands (thiazolidinediones (TZDs)) are important insulin sensitizers and were recently shown to indirectly induce PGC-1β transcription in osteoclasts. Here, we asked whether similar effects occur in adipocytes and show that TZDs also strongly induce PGC-1β in cultured 3T3-L1 cells. This effect, however, differs from the indirect effect proposed for bone and is rapid and direct and involves PPARγ interactions with an intronic PPARγ response element cluster in the PGC-1β locus. TZD treatment of cultured adipocytes results in up-regulation of mitochondrial marker genes, and increased mitochondrial activity and use of short interfering RNA confirms that these effects require PGC-1β. PGC-1β did not participate in PPARγ effects on adipogenesis or lipogenesis, and PGC-1β knockdown did not alter insulin-responsive glucose uptake into 3T3-L1 cells. Similar effects on PGC-1β and mitochondrial gene expression are seen in vivo; fractionation of obese mouse adipose tissue reveals that PPARγ and PGC-1β, but not PGC-1α, are coordinately up-regulated in adipocytes relative to preadipocytes and that TZD treatment induces PGC-1β and mitochondrial marker genes in adipose tissue of obese mice. We propose that PPARγ directly induces PGC-1β expression in adipocytes and that this effect regulates adipocyte mitochondrial activity.
  Journal of Biological Chemistry 06/2011; 286(35):30723-31. · 4.77 Impact Factor
• Article: Fasting insulin reflects heterogeneous physiological processes: role of insulin clearance.

  Mark O Goodarzi, Jinrui Cui, Yii-Der I Chen, Willa A Hsueh, Xiuqing Guo, Jerome I Rotter
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  ABSTRACT: Several processes contribute to variation in fasting insulin concentration, including fasting glucose, insulin resistance, insulin secretion, and insulin clearance. Our goal was to determine the relative contribution of each of these insulin-related traits, plus anthropometric parameters, to fasting insulin among 470 Mexican Americans. The euglycemic hyperinsulinemic clamp yielded insulin sensitivity (M value) and metabolic clearance rate of insulin (MCRI). Acute insulin secretion was estimated by the insulinogenic index (IGI30) from the oral glucose tolerance test. Regression (univariate) and generalized estimating equations (multivariate) were used to describe the relationship of insulin-related traits to fasting insulin. Univarate analyses were used to select which traits to include in the multivariate model. In multivariate analysis, MCRI, M, BMI, waist circumference, and fasting glucose were independently associated with fasting insulin. Decreasing M and MCRI were associated with increasing fasting insulin, whereas increasing BMI, waist circumference, and fasting glucose were associated with increasing fasting insulin. Standardized coefficients allowed determination of the relative strength of each trait's association with fasting insulin in the entire cohort (strongest to weakest): MCRI (-0.35, P < 0.0001), M (-0.24, P < 0.0001), BMI (0.20, P = 0.0011), waist circumference (0.16, P = 0.021), and fasting glucose (0.11, P = 0.014). Fasting insulin is a complex phenotype influenced by several independent processes, each of which might have its own environmental and genetic determinants. One of the most associated traits was insulin clearance, which has implications for studies that have used fasting insulin as a surrogate for insulin resistance.
  AJP Endocrinology and Metabolism 05/2011; 301(2):E402-8. · 4.75 Impact Factor
• Article: Renin-Angiotensin-aldosterone system in diabetes and hypertension.

  Willa A Hsueh, Kathleen Wyne
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  ABSTRACT: Activation of the renin-angiotensin-aldosterone system (RAAS) is the primary etiologic event in the development of hypertension in people with diabetes mellitus. Modulation of the RAAS has been shown to slow the progression and even cause regression of the microvascular and macrovascular complications associated with diabetes mellitus. Early pharmacotherapy with agents that decrease RAAS activation in the adipose tissue have had a dramatic impact on the prevalence of diabetes related complications. Recent data show that preventing the development of "angry fat" can prevent not just hypertension but also type 2 diabetes mellitus and its associated complications. This review updates what is known about angry fat and the role of RAAS inhibition in preventing the metabolic sequelae of local RAAS activation.
  Journal of Clinical Hypertension 04/2011; 13(4):224-37. · 1.83 Impact Factor
• Article: CRTC3 links catecholamine signalling to energy balance.

  Youngsup Song, Judith Altarejos, Mark O Goodarzi, Hiroshi Inoue, Xiuqing Guo, Rebecca Berdeaux, Jeong-Ho Kim, Jason Goode, Motoyuki Igata, Jose C Paz, [......], Naomi Goebel, Lili Vera, Nina Miller, Jinrui Cui, Michelle R Jones, Yii-Der I Chen, Kent D Taylor, Willa A Hsueh, Jerome I Rotter, Marc Montminy
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  ABSTRACT: The adipose-derived hormone leptin maintains energy balance in part through central nervous system-mediated increases in sympathetic outflow that enhance fat burning. Triggering of β-adrenergic receptors in adipocytes stimulates energy expenditure by cyclic AMP (cAMP)-dependent increases in lipolysis and fatty-acid oxidation. Although the mechanism is unclear, catecholamine signalling is thought to be disrupted in obesity, leading to the development of insulin resistance. Here we show that the cAMP response element binding (CREB) coactivator Crtc3 promotes obesity by attenuating β-adrenergic receptor signalling in adipose tissue. Crtc3 was activated in response to catecholamine signals, when it reduced adenyl cyclase activity by upregulating the expression of Rgs2, a GTPase-activating protein that also inhibits adenyl cyclase activity. As a common human CRTC3 variant with increased transcriptional activity is associated with adiposity in two distinct Mexican-American cohorts, these results suggest that adipocyte CRTC3 may play a role in the development of obesity in humans.
  Nature 12/2010; 468(7326):933-9. · 36.28 Impact Factor
• Article: Rosiglitazone attenuates age- and diet-associated nonalcoholic steatohepatitis in male low-density lipoprotein receptor knockout mice.

  Anisha A Gupte, Joey Z Liu, Yuelan Ren, Laurie J Minze, Jessica R Wiles, Alan R Collins, Christopher J Lyon, Domenico Pratico, Milton J Finegold, Stephen T Wong, Paul Webb, John D Baxter, David D Moore, Willa A Hsueh
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  ABSTRACT: Nonalcoholic fatty liver disease (NAFLD) is a common complication of obesity that can progress to nonalcoholic steatohepatitis (NASH), a serious liver pathology that can advance to cirrhosis. The mechanisms responsible for NAFLD progression to NASH remain unclear. Lack of a suitable animal model that faithfully recapitulates the pathophysiology of human NASH is a major obstacle in delineating mechanisms responsible for progression of NAFLD to NASH and, thus, development of better treatment strategies. We identified and characterized a novel mouse model, middle-aged male low-density lipoprotein receptor (LDLR)(-/-) mice fed a high-fat diet (HFD), which developed NASH associated with four of five metabolic syndrome (MS) components. In these mice, as observed in humans, liver steatosis and oxidative stress promoted NASH development. Aging exacerbated the HFD-induced NASH such that liver steatosis, inflammation, fibrosis, oxidative stress, and liver injury markers were greatly enhanced in middle-aged versus young LDLR(-/-) mice. Although expression of genes mediating fatty acid oxidation and antioxidant responses were up-regulated in young LDLR(-/-) mice fed HFD, they were drastically reduced in MS mice. However, similar to recent human trials, NASH was partially attenuated by an insulin-sensitizing peroxisome proliferator-activated receptor-gamma (PPARγ) ligand, rosiglitazone. In addition to expected improvements in MS, newly identified mechanisms of PPARγ ligand effects included stimulation of antioxidant gene expression and mitochondrial β-oxidation, and suppression of inflammation and fibrosis. LDLR-deficiency promoted NASH, because middle-aged C57BL/6 mice fed HFD did not develop severe inflammation and fibrosis, despite increased steatosis. Conclusion: MS mice represent an ideal model to investigate NASH in the context of MS, as commonly occurs in human disease, and NASH development can be substantially attenuated by PPARγ activation, which enhances β-oxidation.
  Hepatology 08/2010; 52(6):2001-11. · 11.66 Impact Factor
• Article: Prediabetes: the importance of early identification and intervention.

  Willa A Hsueh, Laurie Orloski, Kathleen Wyne
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  ABSTRACT: Prediabetes is a state of abnormal glucose homeostasis characterized by the presence of impaired fasting glucose, impaired glucose tolerance, or both. Individuals with prediabetes are at increased risk for type 2 diabetes, compared with individuals with normal glucose values (normal fasting plasma glucose, < 100 mg/dL [5.6 mmol/L]). The increased risk for cardiovascular disease in prediabetes is multifactorial, with etiologies including insulin resistance, hyperglycemia, dyslipidemia, hypertension, systemic inflammation, and oxidative stress. The preferred treatment is intensive lifestyle management and aggressive pharmacologic therapies directed toward individual coronary heart disease risk factors. The use of antihyperglycemic agents in this setting is a topic of intense debate. This review discusses the pathophysiology of prediabetes and its clinical implications, highlighting the importance of early identification and intervention.
  Postgraduate Medicine 07/2010; 122(4):129-43. · 1.78 Impact Factor
• Article: Critical role for osteopontin in diabetic nephropathy.

  Susanne B Nicholas, Joey Liu, Jason Kim, Yuelan Ren, Alan R Collins, Lam Nguyen, Willa A Hsueh
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  ABSTRACT: The profibrotic adhesion molecule, osteopontin (OPN), is upregulated in kidneys of humans and mice with diabetes. The thiazolidinedione (TZD) insulin sensitizers decrease albuminuria in diabetic nephropathy (DN) and reduce OPN expression in vascular and cardiac tissue. To examine whether OPN is a critical mediator of DN we treated db/db mice with insulin, rosiglitazone, or pioglitazone to achieve similar fasting plasma glucose levels. The urine albumin-to-creatinine ratio and glomerular OPN expression were increased in diabetic mice, but both were reduced by the TZDs more than by insulin. We administered streptozotocin to OPN-null and OPN-wild-type mice, and OPN-null mice were bred into both type 1 (Ins2(akita/+)) and 2 (db/db) diabetic mice. In each case, OPN deletion decreased albuminuria, mesangial area, and glomerular collagen IV, fibronectin and transforming growth factor (TGF)-beta in the diabetic mice compared with their respective controls. In cultured mouse mesangial cells, TZDs but not insulin decreased angiotensin II-induced OPN expression, while recombinant OPN upregulated TGF-beta, ERK/MAPK, and JNK/MAPK signaling. These studies show that OPN expression in DN mouse models enhances glomerular damage, likely through the expression of TGF-beta, while its deletion protects against disease progression, suggesting that OPN might serve as a therapeutic target.
  Kidney International 04/2010; 77(7):588-600. · 6.61 Impact Factor
• Article: Age-accelerated atherosclerosis correlates with failure to upregulate antioxidant genes.

  Alan R Collins, Christopher J Lyon, Xuefeng Xia, Joey Z Liu, Rajendra K Tangirala, Fen Yin, Rima Boyadjian, Alfiya Bikineyeva, Domenico Praticò, David G Harrison, Willa A Hsueh
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  ABSTRACT: Excess food intake leads to obesity and diabetes, both of which are well-known independent risk factors for atherosclerosis, and both of which are growing epidemics in an aging population. We hypothesized that aging enhances the metabolic and vascular effects of high fat diet (HFD) and therefore examined the effect of age on atherosclerosis and insulin resistance in lipoprotein receptor knockout (LDLR(-/-)) mice. We found that 12-month-old (middle-aged) LDLR(-/-) mice developed substantially worse metabolic syndrome, diabetes, and atherosclerosis than 3-month-old (young) LDLR(-/-) mice when both were fed HFD for 3 months, despite similar elevations in total cholesterol levels. Microarray analyses were performed to analyze the mechanism responsible for the marked acceleration of atherosclerosis in middle-aged mice. Chow-fed middle-aged mice had greater aortic expression of multiple antioxidant genes than chow-fed young mice, including glutathione peroxidase-1 and -4, catalase, superoxide dismutase-2, and uncoupling protein-2. Aortic expression of these enzymes markedly increased in young mice fed HFD but decreased or only modestly increased in middle-aged mice fed HFD, despite the fact that systemic oxidative stress and vascular reactive oxygen species generation, measured by plasma F2alpha isoprostane concentration (systemic) and dihydroethidium conversion and p47phox expression (vascular), were greater in middle-aged mice fed HFD. Thus, the mechanism for the accelerated vascular injury in older LDLR(-/-) mice was likely the profound inability to mount an antioxidant response. This effect was related to a decrease in vascular expression of 2 key transcriptional pathways regulating the antioxidant response, DJ-1 and forkhead box, subgroup O family (FOXOs). Treatment of middle-aged mice fed HFD with the antioxidant apocynin attenuated atherosclerosis, whereas treatment with the insulin sensitizer rosiglitazone attenuated both metabolic syndrome and atherosclerosis. Both treatments decreased oxidative stress. A novel effect of rosiglitazone was to increase expression of Nrf2 (nuclear factor [erythroid-derived 2]-like 2), a downstream target of DJ-1 contributing to enhanced expression of vascular antioxidant enzymes. This investigation underscores the role of oxidative stress when multiple atherosclerotic risk factors, particularly aging, converge on the vessel wall and emphasizes the need to develop effective strategies to inhibit oxidative stress to protect aging vasculature.
  Circulation Research 04/2009; 104(6):e42-54. · 9.49 Impact Factor
• Article: A Dominant-Negative PPARγ Mutant Promotes Cell Cycle Progression and Cell Growth in Vascular Smooth Muscle Cells

  Joey Z Liu, Christopher J Lyon, Willa A Hsueh, Ronald E Law
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  ABSTRACT: PPARγ ligands have been shown to have antiproliferative effects on many cell types. We herein report that a synthetic dominant-negative (DN) PPARγ mutant functions like a growth factor to promote cell cycle progression and cell proliferation in human coronary artery smooth muscle cells (CASMCs). In quiescent CASMCs, adenovirus-expressed DN-PPARγ promoted G1→S cell cycle progression, enhanced BrdU incorporation, and increased cell proliferation. DN-PPARγ expression also markedly enhanced positive regulators of the cell cycle, increasing Rb and CDC2 phosphorylation and the expression of cyclin A, B1, D1, and MCM7. Conversely, overexpression of wild-type (WT) or constitutively-active (CA) PPARγ inhibited cell cycle progression and the activity and expression of positive regulators of the cell cycle. DN-PPARγ expression, however, did not up-regulate positive cell cycle regulators in PPARγ-deficient cells, strongly suggesting that DN-PPARγ effects on cell cycle result from blocking the function of endogenous wild-type PPARγ. DN-PPARγ expression enhanced phosphorylation of ERK MAPKs. Furthermore, the ERK specific-inhibitor PD98059 blocked DN-PPARγ-induced phosphorylation of Rb and expression of cyclin A and MCM7. Our data thus suggest that DN-PPARγ promotes cell cycle progression and cell growth in CASMCs by modulating fundamental cell cycle regulatory proteins and MAPK mitogenic signaling pathways in vascular smooth muscle cells (VSMCs).
  PPAR Research. 01/2009;
• Source

  Available from: PubMed Central

  Article: A Dominant-Negative PPARgamma Mutant Promotes Cell Cycle Progression and Cell Growth in Vascular Smooth Muscle Cells.

  Joey Z Liu, Christopher J Lyon, Willa A Hsueh, Ronald E Law
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  ABSTRACT: PPARgamma ligands have been shown to have antiproliferative effects on many cell types. We herein report that a synthetic dominant-negative (DN) PPARgamma mutant functions like a growth factor to promote cell cycle progression and cell proliferation in human coronary artery smooth muscle cells (CASMCs). In quiescent CASMCs, adenovirus-expressed DN-PPARgamma promoted G1-->S cell cycle progression, enhanced BrdU incorporation, and increased cell proliferation. DN-PPARgamma expression also markedly enhanced positive regulators of the cell cycle, increasing Rb and CDC2 phosphorylation and the expression of cyclin A, B1, D1, and MCM7. Conversely, overexpression of wild-type (WT) or constitutively-active (CA) PPARgamma inhibited cell cycle progression and the activity and expression of positive regulators of the cell cycle. DN-PPARgamma expression, however, did not up-regulate positive cell cycle regulators in PPARgamma-deficient cells, strongly suggesting that DN-PPARgamma effects on cell cycle result from blocking the function of endogenous wild-type PPARgamma. DN-PPARgamma expression enhanced phosphorylation of ERK MAPKs. Furthermore, the ERK specific-inhibitor PD98059 blocked DN-PPARgamma-induced phosphorylation of Rb and expression of cyclin A and MCM7. Our data thus suggest that DN-PPARgamma promotes cell cycle progression and cell growth in CASMCs by modulating fundamental cell cycle regulatory proteins and MAPK mitogenic signaling pathways in vascular smooth muscle cells (VSMCs).
  PPAR Research 01/2009; 2009:438673. · 2.73 Impact Factor
• Article: Pharmacologic treatment options for prediabetes.

  Willa A Hsueh, Yehuda Handelsman
  Nature Clinical Practice Endocrinology &#38 Metabolism 07/2008; 4(7):380-1. · 7.55 Impact Factor
• Source

  Available from: Evren Caglayan

  Article: Differential roles of cardiomyocyte and macrophage peroxisome proliferator-activated receptor gamma in cardiac fibrosis.

  Evren Caglayan, Bradley Stauber, Alan R Collins, Christopher J Lyon, Fen Yin, Joey Liu, Stephan Rosenkranz, Erland Erdmann, Leif E Peterson, Robert S Ross, Rajendra K Tangirala, Willa A Hsueh
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  ABSTRACT: Cardiac fibrosis is an important component of diabetic cardiomyopathy. Peroxisome proliferator-activated receptor gamma (PPARgamma) ligands repress proinflammatory gene expression, including that of osteopontin, a known contributor to the development of myocardial fibrosis. We thus investigated the hypothesis that PPARgamma ligands could attenuate cardiac fibrosis. Wild-type cardiomyocyte- and macrophage-specific PPARgamma(-/-) mice were infused with angiotensin II (AngII) to promote cardiac fibrosis and treated with the PPARgamma ligand pioglitazone to determine the roles of cardiomyocyte and macrophage PPARgamma in cardiac fibrosis. Cardiomyocyte-specific PPARgamma(-/-) mice (cPPARgamma(-/-)) developed spontaneous cardiac hypertrophy with increased ventricular osteopontin expression and macrophage content, which were exacerbated by AngII infusion. Pioglitazone attenuated AngII-induced fibrosis, macrophage accumulation, and osteopontin expression in both wild-type and cPPARgamma(-/-) mice but induced hypertrophy in a PPARgamma-dependent manner. We pursued two mechanisms to explain the antifibrotic cardiomyocyte-PPARgamma-independent effects of pioglitazone: increased adiponectin expression and attenuation of proinflammatory macrophage activity. Adenovirus-expressed adiponectin had no effect on cardiac fibrosis and the PPARgamma ligand pioglitazone did not attenuate AngII-induced cardiac fibrosis, osteopontin expression, or macrophage accumulation in monocyte-specific PPARgamma(-/-) mice. We arrived at the following conclusions: 1) both cardiomyocyte-specific PPARgamma deficiency and activation promote cardiac hypertrophy, 2) both cardiomyocyte and monocyte PPARgamma regulate cardiac macrophage infiltration, 3) inflammation is a key mediator of AngII-induced cardiac fibrosis, 4) macrophage PPARgamma activation prevents myocardial macrophage accumulation, and 5) PPARgamma ligands attenuate AngII-induced cardiac fibrosis by inhibiting myocardial macrophage infiltration. These observations have important implications for potential interventions to prevent cardiac fibrosis.
  Diabetes 06/2008; 57(9):2470-9. · 8.29 Impact Factor
• Article: Carotid intima-media thickness (cIMT) cosegregates with blood pressure and renal function in hypertensive Hispanic families.

  Yi-Chun Chen, Xiuqing Guo, Leslie J Raffel, Anny H Xiang, Belle Fang, Willa A Hsueh, Kent D Taylor, Thomas A Buchanan, Howard N Hodis, Jerome I Rotter
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  ABSTRACT: Carotid intima-media thickness (cIMT) is commonly used as a surrogate for atherosclerosis. Since cIMT is correlated with hypertension and microalbuminuria, we tested the hypothesis that there is a genetic basis for the observed relationship between cIMT, blood pressure (BP), and renal function within high risk families. Six hundred and three nondiabetic individuals from 149 Hispanic American families (HA) were ascertained via a hypertensive parent. Phenotyping included cIMT, BP, anthropometrics, and renal function, which was assessed by urine microalbumin, blood urea nitrogen (BUN), serum creatinine (Cr), and Cr clearance (Ccr). A variance components approach was used to estimate trait heritabilities and decompositions of their phenotypic correlations. Significant heritabilities (P<0.0001 for each) were found for cIMT, body mass index, BP, and the renal function traits. There were significant phenotypic correlations within family members, with positive correlations between cIMT and systolic BP (SBP), and urine microalbumin and Ccr, and negative correlations among cIMT, BUN, and Cr; these remained significant after correction for BP, but not after correction for urine microalbumin. Partitioned into genetic and environmental correlations, genetic correlations were significant between cIMT and each of SBP, urine microalbumin, Ccr, BUN, and Cr, respectively, while there were significant environmental correlations between cIMT and each of BUN, Cr, and Ccr. The genetic and environmental correlations were unchanged when adjusted for BP, but were no longer significant when adjusted for urine microalbumin. There is substantial genetic contribution to SBP, renal function, and cIMT in these high risk Hispanic families. Subclinical atherosclerosis shares common genetic determinants with SBP and, independently, with measures of renal function.
  Atherosclerosis 05/2008; 198(1):160-5. · 3.79 Impact Factor
• Article: PPARdelta-mediated antiinflammatory mechanisms inhibit angiotensin II-accelerated atherosclerosis.

  Yasunori Takata, Joey Liu, Fen Yin, Alan R Collins, Christopher J Lyon, Chih-Hao Lee, Annette R Atkins, Michael Downes, Grant D Barish, Ronald M Evans, Willa A Hsueh, Rajendra K Tangirala
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  ABSTRACT: Activation of the nuclear hormone receptor peroxisome proliferator-activated receptor delta (PPARdelta) has been shown to improve insulin resistance, adiposity, and plasma HDL levels. However, its antiatherogenic role remains controversial. Here we report atheroprotective effects of PPARdelta activation in a model of angiotensin II (AngII)-accelerated atherosclerosis, characterized by increased vascular inflammation related to repression of an antiinflammatory corepressor, B cell lymphoma-6 (Bcl-6), and the regulators of G protein-coupled signaling (RGS) proteins RGS4 and RGS5. In this model, administration of the PPARdelta agonist GW0742 (1 or 10 mg/kg) substantially attenuated AngII-accelerated atherosclerosis without altering blood pressure and increased vascular expression of Bcl-6, RGS4, and RGS5, which was associated with suppression of inflammatory and atherogenic gene expression in the artery. In vitro studies demonstrated similar changes in AngII-treated macrophages: PPARdelta activation increased both total and free Bcl-6 levels and inhibited AngII activation of MAP kinases, p38, and ERK1/2. These studies uncover crucial proinflammatory mechanisms of AngII and highlight actions of PPARdelta activation to inhibit AngII signaling, which is atheroprotective.
  Proceedings of the National Academy of Sciences 04/2008; 105(11):4277-82. · 9.68 Impact Factor
• Article: SORCS1: a novel human type 2 diabetes susceptibility gene suggested by the mouse.

  Mark O Goodarzi, Donna M Lehman, Kent D Taylor, Xiuqing Guo, Jinrui Cui, Manuel J Quiñones, Susanne M Clee, Brian S Yandell, John Blangero, Willa A Hsueh, Alan D Attie, Michael P Stern, Jerome I Rotter
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  ABSTRACT: A small number of susceptibility genes for human type 2 diabetes have been identified by candidate gene analysis or positional cloning. Genes found to influence diabetes or related traits in mice are likely to be susceptibility genes in humans. SorCS1 is the gene identified as responsible for the mouse chromosome 19 T2dm2 quantitative trait locus for fasting insulin levels, acting via impaired insulin secretion and increased islet disruption in obese females. Genes that impair compensatory insulin secretion in response to obesity-induced insulin resistance may be particularly relevant to human diabetes. Thus, we sought to determine whether variation in the human SORCS1 gene was associated with diabetes-related traits. We assessed the contribution of variation in SORCS1 to human insulin-related traits in two distinct Mexican-American cohorts. One cohort (the Mexican-American Coronary Artery Disease [MACAD] cohort) consisted of nondiabetic individuals, allowing assessment of genetic association with subclinical intermediate insulin-related traits; the second cohort (the San Antonio Family Diabetes Study [SAFADS]) contained individuals with diabetes, allowing association analyses with overt disease. We first found association of SORCS1 single nucleotide polymorphisms and haplotypes with fasting insulin levels and insulin secretion in the MACAD cohort. Similar to our results in the mice, the genetic association was strongest in overweight women. We then observed association with diabetes risk and age at diagnosis in women of the SAFADS cohort. Identification of SORCS1 as a novel gene affecting insulin secretion and diabetes risk is likely to provide important insight into the biology of obesity-induced type 2 diabetes.
  Diabetes 07/2007; 56(7):1922-9. · 8.29 Impact Factor