Dr. Wang is a postdoctoral scholar in the Division of Vascular Surgery at Stanford University Medical Center. She obtained her PhD at University of British Columbia, Canada, where she gained training in basic science research and leading multidisciplinary research. Then she joined the lab of Dr. Gordon Francis as a postdoctoral fellow at Centre for Heart Lung Innovation, St. Paul’s Hospital, Canada, to obtain experience in translational research. She examined the role of vascular smooth muscle cells in atherogenesis as a potential therapeutic target to prevent cholesterol accumulation. This work has won her the Early Career Investigator Award at the 2016 American Heart Association Scientific Session.
Under the guidance of Prof. Nicholas Leeper, the overall goal of Dr. Wang’s research is to determine the mechanistic pathways driving smooth muscle cell accumulation during atherogenesis, and the clinical relevance of these pathways using a combination of high throughput gene expression profiling, bioinformatics analysis, and molecular biology on lineage-tracing mouse model and human biospecimens.
Honors & Awards
Postdoctoral Fellowship, American Heart Association and VIVA Physician (2018-2020)
ATVB Early Career Investigator Award, American Heart Association (2016)
Postdoctoral Fellowship, Michael Smith Foundation for Health Research (2015-2017)
Dr. William Wilson Simson Memorial Award, University of British Columbia (2013)
Doctoral Student Research Award, Canadian Diabetes Association (2012-2014)
Four Year Doctoral Fellowship, University of British Columbia (2011-2013)
Boards, Advisory Committees, Professional Organizations
Member, American Heart Association (2016 - Present)
Bachelor of Science, Wuhan University (2006)
Doctor of Philosophy, University of British Columbia (2014)
Master of Science, Wuhan University (2008)
- Clonal Smooth Muscle Cell Expansion, Autophagy, and Vascular Integrity in Aortic Aneurysm Disease. Arteriosclerosis, thrombosis, and vascular biology 2019; 39 (6): 982–83
Smooth Muscle Cells Contribute the Majority of Foam Cells in ApoE (Apolipoprotein E)-Deficient Mouse Atherosclerosis.
Arteriosclerosis, thrombosis, and vascular biology
2019; 39 (5): 876–87
Objective- Smooth muscle cells (SMCs) are the most abundant cells in human atherosclerotic lesions and are suggested to contribute at least 50% of atheroma foam cells. In mice, SMCs contribute fewer total lesional cells. The purpose of this study was to determine the contribution of SMCs to total foam cells in apolipoprotein E-deficient (ApoE-/-) mice, and the utility of these mice to model human SMC foam cell biology and interventions. Approach and Results- Using flow cytometry, foam cells in the aortic arch of ApoE-/- mice were characterized based on the expression of leukocyte-specific markers. Nonleukocyte foam cells increased from 37% of total foam cells in 27-week-old to 75% in 57-week-old male ApoE-/- mice fed a chow diet and were ≈70% in male and female ApoE-/- mice following 6 weeks of Western diet feeding. A similar contribution to total foam cells by SMCs was found using SMC-lineage tracing ApoE-/- mice fed the Western diet for 6 or 12 weeks. Nonleukocyte foam cells contributed a similar percentage of total atheroma cholesterol and exhibited lower expression of the cholesterol exporter ABCA1 (ATP-binding cassette transporter A1) when compared with leukocyte-derived foam cells. Conclusions- Consistent with previous studies of human atheromas, we present evidence that SMCs contribute the majority of atheroma foam cells in ApoE-/- mice fed a Western diet and a chow diet for longer periods. Reduced expression of ABCA1, also seen in human intimal SMCs, suggests a common mechanism for formation of SMC foam cells across species, and represents a novel target to enhance atherosclerosis regression.
View details for PubMedID 30786740
- Proefferocytic Therapy Promotes Transforming Growth Factor-beta Signaling and Prevents Aneurysm Formation CIRCULATION 2018; 137 (7): 750–53
Intrinsic and extrinsic regulation of cardiac lipoprotein lipase following diabetes
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS
2015; 1851 (2): 163-171
Cardiac lipoprotein lipase (LPL) is a pivotal enzyme controlling heart metabolism by providing the majority of fatty acids required by this organ. From activation in cardiomyocytes to secretion to the vascular lumen, cardiac LPL is regulated by multiple pathways, which are altered during diabetes. Hence, dimerization/activation of LPL is modified following diabetes, a process controlled by lipase maturation factor 1. The role of AMP-activated protein kinase, protein kinase D, and heparan sulfate proteoglycans, intrinsic factors that regulate the intracellular transport of LPL is also shifted, and is discussed. More recent studies have identified several exogenous factors released from endothelial cells (EC) and adipose tissue that are required for proper functioning of LPL. In response to hyperglycemia, both active and latent heparanase are released from EC to facilitate LPL secretion. Diabetes also increased the expression of glycosylphosphatidylinositol-anchored high density lipoprotein-binding protein 1 (GPIHBP1) in EC, which mediates the transport of LPL across EC. Angiopoietin-like protein 4 secreted from the adipose tissue has the potential to reduce coronary LPL activity. Knowledge of these intrinsic and extrinsic factors could be used develop therapeutic targets to normalize LPL function, and maintain cardiac energy homeostasis after diabetes.
View details for DOI 10.1016/j.bbalip.2014.11.007
View details for Web of Science ID 000348963600006
View details for PubMedID 25463481
Endothelial Cell Heparanase Taken Up by Cardiomyocytes Regulates Lipoprotein Lipase Transfer to the Coronary Lumen After Diabetes
2014; 63 (8): 2643-2655
After diabetes, the heart has a singular reliance on fatty acid (FA) for energy production, which is achieved by increased coronary lipoprotein lipase (LPL) that breaks down circulating triglycerides. Coronary LPL originates from cardiomyocytes, and to translocate to the vascular lumen, the enzyme requires liberation from myocyte surface heparan sulfate proteoglycans (HSPGs), an activity that needs to be sustained after chronic hyperglycemia. We investigated the mechanism by which endothelial cells (EC) and cardiomyocytes operate together to enable continuous translocation of LPL after diabetes. EC were cocultured with myocytes, exposed to high glucose, and uptake of endothelial heparanase into myocytes was determined. Upon uptake, the effect of nuclear entry of heparanase was also investigated. A streptozotocin model of diabetes was used to expand our in vitro observations. In high glucose, EC-derived latent heparanase was taken up by cardiomyocytes by a caveolae-dependent pathway using HSPGs. This latent heparanase was converted into an active form in myocyte lysosomes, entered the nucleus, and upregulated gene expression of matrix metalloproteinase-9. The net effect was increased shedding of HSPGs from the myocyte surface, releasing LPL for its onwards translocation to the coronary lumen. EC-derived heparanase regulates the ability of the cardiomyocyte to send LPL to the coronary lumen. This adaptation, although acutely beneficial, could be catastrophic chronically because excess FA causes lipotoxicity. Inhibiting heparanase function could offer a new strategy for managing cardiomyopathy observed after diabetes.
View details for DOI 10.2337/db13-1842
View details for Web of Science ID 000340262100015
View details for PubMedID 24608441
Endothelial cells respond to hyperglycemia by increasing the LPL transporter GPIHBP1
AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM
2014; 306 (11): E1274-E1283
In diabetes, when glucose uptake and oxidation are impaired, the heart is compelled to use fatty acid (FA) almost exclusively for ATP. The vascular content of lipoprotein lipase (LPL), the rate-limiting enzyme that determines circulating triglyceride clearance, is largely responsible for this FA delivery and increases following diabetes. Glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein [GPIHBP1; a protein expressed abundantly in the heart in endothelial cells (EC)] collects LPL from the interstitial space and transfers it across ECs onto the luminal binding sites of these cells, where the enzyme is functional. We tested whether ECs respond to hyperglycemia by increasing GPIHBP1. Streptozotocin diabetes increased cardiac LPL activity and GPIHBP1 gene and protein expression. The increased LPL and GPIHBP1 were located at the capillary lumen. In vitro, passaging EC caused a loss of GPIHBP1, which could be induced on exposure to increasing concentrations of glucose. The high-glucose-induced GPIHBP1 increased LPL shuttling across EC monolayers. GPIHBP1 expression was linked to the EC content of heparanase. Moreover, active heparanase increased GPIHBP1 gene and protein expression. Both ECs and myocyte heparan sulfate proteoglycan-bound platelet-derived growth factor (PDGF) released by heparanase caused augmentation of GPIHBP1. Overall, our data suggest that this protein "ensemble" (heparanase-PDGF-GPIHBP1) cooperates in the diabetic heart to regulate FA delivery and utilization by the cardiomyocytes. Interrupting this axis may be a novel therapeutic strategy to restore metabolic equilibrium, curb lipotoxicity, and help prevent or delay heart dysfunction that is characteristic of diabetes.
View details for DOI 10.1152/ajpendo.00007.2014
View details for Web of Science ID 000337897000006
View details for PubMedID 24735886
Hyperglycemia-Induced Secretion of Endothelial Heparanase Stimulates a Vascular Endothelial Growth Factor Autocrine Network in Cardiomyocytes That Promotes Recruitment of Lipoprotein Lipase
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
2013; 33 (12): 2830-2838
During diabetes mellitus, coronary lipoprotein lipase increases to promote the predominant use of fatty acids. We have reported that high glucose stimulates active heparanase secretion from endothelial cells to cleave cardiomyocyte heparan sulfate and release bound lipoprotein lipase for transfer to the vascular lumen. In the current study, we examined whether heparanase also has a function to release cardiomyocyte vascular endothelial growth factor (VEGF), and whether this growth factor influences cardiomyocyte fatty acid delivery in an autocrine manner.Acute, reversible hyperglycemia was induced in rats, and a modified Langendorff heart perfusion was used to separate the coronary perfusate from the interstitial effluent. Coronary artery endothelial cells were exposed to high glucose to generate conditioned medium, and VEGF release from isolated cardiomyocytes was tested using endothelial cell conditioned medium or purified active and latent heparanase. Autocrine signaling of myocyte-derived VEGF on cardiac metabolism was studied. High glucose promoted latent and active heparanase secretion into endothelial cell conditioned medium, an effective stimulus for releasing cardiomyocyte VEGF. Intriguingly, latent heparanase was more efficient than active heparanase in releasing VEGF from a unique cell surface pool. VEGF augmented cardiomyocyte intracellular calcium and AMP-activated protein kinase phosphorylation and increased heparin-releasable lipoprotein lipase.Our data suggest that the heparanase-lipoprotein lipase-VEGF axis amplifies fatty acid delivery, a rapid and adaptive mechanism that is geared to overcome the loss of glucose consumption by the diabetic heart. If prolonged, the resultant lipotoxicity could lead to cardiovascular disease in humans.
View details for DOI 10.1161/ATVBAHA.113.302222
View details for Web of Science ID 000329283900019
View details for PubMedID 24115032
Endothelial Heparanase Regulates Heart Metabolism by Stimulating Lipoprotein Lipase Secretion From Cardiomyocytes
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
2013; 33 (5): 894-U77
After diabetes mellitus, transfer of lipoprotein lipase (LPL) from cardiomyocytes to the coronary lumen increases, and this requires liberation of LPL from the myocyte surface heparan sulfate proteoglycans with subsequent replenishment of this reservoir. At the lumen, LPL breaks down triglyceride to meet the increased demand of the heart for fatty acid. Here, we examined the contribution of coronary endothelial cells (ECs) toward regulation of cardiomyocyte LPL secretion.Bovine coronary artery ECs were exposed to high glucose, and the conditioned medium was used to treat cardiomyocytes. EC-conditioned medium liberated LPL from the myocyte surface, in addition to facilitating its replenishment. This effect was attributed to the increased heparanase content in EC-conditioned medium. Of the 2 forms of heparanase secreted from EC in response to high glucose, active heparanase released LPL from the myocyte surface, whereas latent heparanase stimulated reloading of LPL from an intracellular pool via heparan sulfate proteoglycan-mediated RhoA activation.Endothelial heparanase is a participant in facilitating LPL increase at the coronary lumen. These observations provide an insight into the cross-talk between ECs and cardiomyocytes to regulate cardiac metabolism after diabetes mellitus.
View details for DOI 10.1161/ATVBAHA.113.301309
View details for Web of Science ID 000317476000009
View details for PubMedID 23471235
A Role for Hepatic Leptin Signaling in Lipid Metabolism via Altered Very Low Density Lipoprotein Composition and Liver Lipase Activity in Mice
2013; 57 (2): 543-554
Obesity is highly associated with dyslipidemia and cardiovascular disease. However, the mechanism behind this association is not completely understood. The hormone leptin may be a molecular link between obesity and dysregulation of lipid metabolism. Leptin can affect lipid metabolism independent of its well-known effects on food intake and energy expenditure, but exactly how this occurs is ill-defined. We hypothesized that since leptin receptors are found on the liver and the liver plays an integral role in regulating lipid metabolism, leptin may affect lipid metabolism by acting directly on the liver. To test this hypothesis, we generated mice with a hepatocyte-specific loss of leptin signaling. We previously showed that these mice have increased insulin sensitivity and elevated levels of liver triglycerides compared with controls. Here, we show that mice lacking hepatic leptin signaling have decreased levels of plasma apolipoprotein B yet increased levels of very low density lipoprotein (VLDL) triglycerides, suggesting alterations in triglyceride incorporation into VLDL or abnormal lipoprotein remodeling in the plasma. Indeed, lipoprotein profiles revealed larger apolipoprotein B-containing lipoprotein particles in mice with ablated liver leptin signaling. Loss of leptin signaling in the liver was also associated with a substantial increase in lipoprotein lipase activity in the liver, which may have contributed to increased lipid droplets in the liver.Lack of hepatic leptin signaling results in increased lipid accumulation in the liver and larger, more triglyceride-rich VLDL particles. Collectively, these data reveal an interesting role for hepatic leptin signaling in modulating triglyceride metabolism.
View details for DOI 10.1002/hep.26043
View details for Web of Science ID 000315643400015
View details for PubMedID 22941940
Lipoprotein lipase mediated fatty acid delivery and its impact in diabetic cardiomyopathy
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS
2012; 1821 (5): 800-808
Although cardiovascular disease is the leading cause of diabetes-related death, its etiology is still not understood. The immediate change that occurs in the diabetic heart is altered energy metabolism where in the presence of impaired glucose uptake, glycolysis, and pyruvate oxidation, the heart switches to exclusively using fatty acids (FA) for energy supply. It does this by rapidly amplifying its lipoprotein lipase (LPL-a key enzyme, which hydrolyzes circulating lipoprotein-triglyceride to release FA) activity at the coronary lumen. An abnormally high capillary LPL could provide excess fats to the heart, leading to a number of metabolic, morphological, and mechanical changes, and eventually to cardiac disease. Unlike the initial response, chronic severe diabetes "turns off" LPL, this is also detrimental to cardiac function. In this review, we describe a number of post-translational mechanisms that influence LPL vesicle formation, actin cytoskeleton rearrangement, and transfer of LPL from cardiomyocytes to the vascular lumen to hydrolyze lipoprotein-triglyceride following diabetes. Appreciating the mechanism of how the heart regulates its LPL following diabetes should allow the identification of novel targets for therapeutic intervention, to prevent heart failure. This article is part of a Special Issue entitled Triglyceride Metabolism and Disease.
View details for DOI 10.1016/j.bbalip.2011.10.001
View details for Web of Science ID 000303028400013
View details for PubMedID 22024251
Fatty Acid-Induced Nuclear Translocation of Heparanase Uncouples Glucose Metabolism in Endothelial Cells
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
2012; 32 (2): 406-U568
Heparanase is an endoglycosidase that specifically cleaves carbohydrate chains of heparan sulfate. We have recently reported that high fatty acid increased the nuclear content of endothelial heparanase. Here, we examined the mechanism and the consequences behind this nuclear translocation of heparanase.Bovine coronary artery endothelial cells were grown to confluence and incubated with palmitic acid. Palmitic acid induced rapid nuclear accumulation of heparanase that was dependent on Bax activation and lysosome permeabilization. Heat shock protein 90 was an important mediator of palmitic acid-induced shuttling of heparanase to the nucleus. Nuclear heparanase promoted cleavage of heparan sulfate, a potent inhibitor of histone acetyltransferase activity and gene transcription. A TaqMan gene expression assay revealed an increase in genes related to glucose metabolism and inflammation. In addition, glycolysis was uncoupled from glucose oxidation, resulting in accumulation of lactate.The results presented in this study demonstrate that fatty acid can provoke lysosomal release of heparanase, its nuclear translocation, activation of genes controlling glucose metabolism, and accumulation of lactate. Given that lactate and inflammation have been implicated in the progression of atherosclerosis, our data may serve to reduce the associated cardiovascular complications seen during diabetes.
View details for DOI 10.1161/ATVBAHA.111.240770
View details for Web of Science ID 000299321200033
View details for PubMedID 22116097
Severity of Diabetes Governs Vascular Lipoprotein Lipase by Affecting Enzyme Dimerization and Disassembly
2011; 60 (8): 2041-2050
In diabetes, when glucose consumption is restricted, the heart adapts to use fatty acid (FA) exclusively. The majority of FA provided to the heart comes from the breakdown of circulating triglyceride (TG), a process catalyzed by lipoprotein lipase (LPL) located at the vascular lumen. The objective of the current study was to determine the mechanisms behind LPL processing and breakdown after moderate and severe diabetes.To induce acute hyperglycemia, diazoxide, a selective, ATP-sensitive K(+) channel opener was used. For chronic diabetes, streptozotocin, a β-cell-specific toxin was administered at doses of 55 or 100 mg/kg to generate moderate and severe diabetes, respectively. Cardiac LPL processing into active dimers and breakdown at the vascular lumen was investigated.After acute hyperglycemia and moderate diabetes, more LPL is processed into an active dimeric form, which involves the endoplasmic reticulum chaperone calnexin. Severe diabetes results in increased conversion of LPL into inactive monomers at the vascular lumen, a process mediated by FA-induced expression of angiopoietin-like protein 4 (Angptl-4).In acute hyperglycemia and moderate diabetes, exaggerated LPL processing to dimeric, catalytically active enzyme increases coronary LPL, delivering more FA to the heart when glucose utilization is compromised. In severe chronic diabetes, to avoid lipid oversupply, FA-induced expression of Angptl-4 leads to conversion of LPL to inactive monomers at the coronary lumen to impede TG hydrolysis. Results from this study advance our understanding of how diabetes changes coronary LPL, which could contribute to cardiovascular complications seen with this disease.
View details for DOI 10.2337/db11-0042
View details for Web of Science ID 000293488100006
View details for PubMedID 21646389
View details for PubMedCentralID PMC3142087
Cardiac triglyceride accumulation following acute lipid excess occurs through activation of a FoxO1-iNOS-CD36 pathway
FREE RADICAL BIOLOGY AND MEDICINE
2011; 51 (2): 352-363
Obesity due to nutrient excess leads to chronic pathologies including type 2 diabetes and cardiovascular disease. Related to nutrient excess, FoxO1 has a role in regulating fatty acid uptake and oxidation and triglyceride (TG) storage by mechanisms that are largely unresolved. We examined the mechanism behind palmitate (PA)-induced TG accumulation in cardiomyocytes. To mimic lipid excess, rat ventricular myocytes were incubated with albumin-bound PA (1 mM) or rats were administered Intralipid (20%). PA-treated cardiomyocytes showed a substantial increase in TG accumulation, accompanied by amplification of nuclear migration of phospho-p38 and FoxO1, iNOS induction, and translocation of CD36 to the plasma membrane. PA also increased Cdc42 protein and its tyrosine nitration, thereby rearranging the cytoskeleton and facilitating CD36 translocation. These effects were duplicated by TNF-α and reversed by the iNOS inhibitor 1400 W. PA increased the nuclear interaction between FoxO1 and NF-κB, reduced the nuclear presence of PGC-1α, and downregulated expression of oxidative phosphorylation proteins. In vivo a robust increase in cardiac TGs after Intralipid administration was also associated with augmentation of nuclear FoxO1 and iNOS expression. Impeding this FoxO1-iNOS-CD36 pathway could decrease cardiac lipid accumulation and oxidative/nitrosative stress and help ameliorate the cardiovascular complications associated with obesity and diabetes.
View details for DOI 10.1016/j.freeradbiomed.2011.04.009
View details for Web of Science ID 000292352500011
View details for PubMedID 21545834
Glucose-induced endothelial heparanase secretion requires cortical and stress actin reorganization
2010; 87 (1): 127-136
Heparanase, which specifically cleaves carbohydrate chains of heparan sulfate, has been implicated in the pathology of diabetes-associated complications. Using high glucose (HG) to replicate hyperglycaemia observed following diabetes, the present study was designed to determine the mechanism by which HG initiates endothelial heparanase secretion.To examine the effect of HG on endothelial heparanase, bovine coronary artery endothelial cells were incubated with 25 mM glucose. Strategies using different agonists and antagonists were used to determine the mechanism behind HG-induced heparanase secretion. In endothelial cells, heparanase colocalized with lysosomes predominately around the nucleus, and HG caused its dispersion towards the plasma membrane for subsequent secretion. ATP release, purinergic receptor activation, cortical actin disassembly, and stress actin formation were essential for this HG-induced heparanase secretion. With HG, phosphorylation of filamin likely contributed to the cortical actin disassembly, whereas Ca(2+)/calmodulin-dependent protein kinase II and p38 mitogen-activated protein kinase /heat shock protein 25 phosphorylation mediated stress actin formation. The endothelial secreted heparanase in response to HG demonstrated endoglucuronidase activity, cleaved heparan sulfate, and released attached proteins like lipoprotein lipase and basic fibroblast growth factor.Our results suggest that HG is a potent stimulator of endothelial heparanase secretion. These data may assist in devising new therapeutic strategies to prevent or delay the cardiovascular complications associated with diabetes.
View details for DOI 10.1093/cvr/cvq051
View details for Web of Science ID 000278690000018
View details for PubMedID 20164120
The Increase in Cardiac Pyruvate Dehydrogenase Kinase-4 after Short-Term Dexamethasone Is Controlled by an Akt-p38-Forkhead Box Other Factor-1 Signaling Axis
2010; 151 (5): 2306-2318
Glucocorticoids increase pyruvate dehydrogenase kinase-4 (PDK4) mRNA and protein expression, which phosphorylates pyruvate dehydrogenase, thereby preventing the formed pyruvate from undergoing mitochondrial oxidation. This increase in PDK4 expression is mediated by the mandatory presence of Forkhead box other factors (FoxOs) in the nucleus. In the current study, we examined the importance of the nongenomic effects of dexamethasone (Dx) in determining the compartmentalization of FoxO and hence its transcriptional activity. Rat cardiomyocytes exposed to Dx produced a robust decrease in glucose oxidation. Measurement of FoxO compartmentalization demonstrated increase in nuclear but resultant decrease in cytosolic content of FoxO1 with no change in the total content. The increase in nuclear content of FoxO1 correlated to an increase in nuclear phospho-p38 MAPK together with a robust association between this transcription factor and kinase. Dx also promoted nuclear retention of FoxO1 through a decrease in phosphorylation of Akt, an effect mediated by heat shock proteins binding to Akt. Measurement of the nuclear and total expression of sirtuin-1 protein showed no change after Dx. Instead, Dx increased the association of sirtuin-1 with FoxO1, thereby causing a decrease in FoxO acetylation. Manipulation of FoxO1 through agents that interfere with its nuclear shuttling or acetylation were effective in reducing Dx-induced increase in PDK4 protein expression. Our data suggest that FoxO1 has a major PDK4-regulating function. In addition, given the recent suggestions that altering glucose use can set the stage for heart failure, manipulating FoxO could assist in devising new therapeutic strategies to optimize cardiac metabolism and prevent PDK4 induced cardiac complications.
View details for DOI 10.1210/en.2009-1072
View details for Web of Science ID 000276902600036
View details for PubMedID 20181797