Jeffrey T Wigle

Jeffrey T Wigle
University of Manitoba | UMN · Department of Biochemistry and Medical Genetics

Doctor of Philosophy

About

90
Publications
6,470
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4,669
Citations
Citations since 2017
19 Research Items
1500 Citations
2017201820192020202120222023050100150200250
2017201820192020202120222023050100150200250
2017201820192020202120222023050100150200250
2017201820192020202120222023050100150200250

Publications

Publications (90)
Article
Full-text available
A decrease in the circulating levels of adiponectin in obesity increases the risk of metabolic complications, but the role of globular adiponectin, a truncated form produced by proteolytic cleavage, has not been defined. The objective of this investigation was to determine how globular adiponectin is generated and to determine whether this process...
Article
Aims In response to pro-fibrotic signals, scleraxis regulates cardiac fibroblast activation in vitro via transcriptional control of key fibrosis genes such as collagen and fibronectin; however, its role in vivo is unknown. The present study assessed the impact of scleraxis loss on fibroblast activation, cardiac fibrosis, and dysfunction in pressure...
Article
Full-text available
Forebrain development in vertebrates is regulated by transcription factors encoded by homeobox, bHLH and forkhead gene families throughout the progressive and overlapping stages of neural induction and patterning, regional specification and generation of neurons and glia from central nervous system (CNS) progenitor cells. Moreover, cell fate decisi...
Article
Full-text available
Atherosclerosis, myocardial infarction (MI) and heart failure (HF) are the main causes of mortality and morbidity around the globe. New therapies are needed to better manage ischemic heart disease and HF as existing strategies are not curative. Resveratrol is a stilbene polyphenolic compound with favorable biological effects that counter chronic di...
Article
Full-text available
The development and progression of heart failure (HF) due to myocardial infarction (MI) is a major concern even with current optimal therapy. Resveratrol is a plant polyphenol with cardioprotective properties. Sacubitril/valsartan is known to be beneficial in chronic HF patients. In this study, we investigated the comparative and combinatorial bene...
Chapter
ObesityObesity is a global epidemic and obese populations are at a much higher risk of developing diseases such as hypertensionHypertension, type 2 diabetes, stroke and congestive heartHeartfailureHeart failure. Increased adiposity is the hallmark of this physiological alteration of the body in response to excess intake of energy rich food, and thi...
Article
Long-chain saturated fatty acids, especially palmitic acid (PA), contribute to cardiomyocyte lipotoxicity. This study tests the effects of PA on adult rat cardiomyocyte contractile function and proteins associated with calcium regulating cardiomyocyte contraction and relaxation. Adult rat cardiomyocytes were pretreated with resveratrol (Resv) and t...
Article
Full-text available
In this study, we tested the potential cardioprotective effects of the phytoalexin resveratrol (Rsv) on primary adult rat cardiac fibroblasts (CF), myofibroblasts (MF) and cardiomyocytes. Adult rat CF and cardiomyocytes were isolated from male 10-week old Sprague–Dawley rats, cultured for either 24 h (cardiomyocytes) or 48 h (CF) before treatments....
Article
Exercise enhances cardiac sarcoplasmic reticulum Ca2+-ATPase 2a (SERCA2a) function through unknown mechanisms. The present study tested the hypothesis that the positive effects of exercise on SERCA2a expression and function in the left ventricle is dependent on adenosine-monophosphate-activated protein kinase (AMPK) α2 function. AMPKα2 kinase-dead...
Article
Cardiovascular disease (CVD) is the number one cause of death in both men and women. Younger women have a lower risk for CVD, but their risk increases considerably after menopause when estrogen levels decrease. The cardiovascular protective properties of estrogen are mediated through decreasing vascular inflammation and progression of atheroscleros...
Chapter
Cardiovascular disease leading to heart failure (HF) remains a leading cause of morbidity and mortality worldwide. Improved pharmacological and interventional coronary procedures have led to improved outcomes following acute myocardial infarction. This success has translated into an unforeseen increased incidence in HF. This review summarizes the s...
Article
Full-text available
Following cardiac injury, fibroblasts are activated and are termed as myofibroblasts, and these cells are key players in extracellular matrix (ECM) remodeling and fibrosis, itself a primary contributor to heart failure. Nutraceuticals have been shown to blunt cardiac fibrosis in both in-vitro and in-vivo studies. However, nutraceuticals have had co...
Article
The present study investigated the effects of cyanidin 3-O-glucoside (C3G) in cardiomyocytes (CM) and fibroblasts exposed to endothelin 1 (ET1), as well as in the spontaneously hypertensive rat (SHR) model, alone or in combination with hydrochlorothiazide (HCT). Adult rat CM and cardiac fibroblasts (CF) were pretreated with C3G and co-incubated wit...
Article
Remodeling of the cardiac extracellular matrix is responsible for a number of the detrimental effects on heart function that arise secondary to hypertension, diabetes and myocardial infarction. This remodeling consists both of an increase in new matrix protein synthesis, and an increase in the expression of matrix metalloproteinases (MMPs) that deg...
Article
Cyanidin 3-0-glucoside (CG) is a polyphenol with potential health benefits. In this study, we investigated, for the first time, the cardioprotective effects of CG in an animal model of myocardial infarction (MI), a major cause of death worldwide. Sham and MI rats were administered CG (10 mg kg⁻¹ day⁻¹) daily for one week prior to surgery, and 8 wee...
Article
In the vascular system, ageing is accompanied by the accrual of senescent cells and is associated with an increased risk of vascular disease. Endothelial cell (EC) dysfunction is a hallmark of vascular disease and is characterized by decreased angiogenic potential, reduced nitric oxide bioavailability, impaired vasodilation, increased production of...
Article
Full-text available
Regulated retinal ganglion cell (RGC) differentiation and axonal guidance is required for a functional visual system. Homeodomain and basic helix loop helix transcription factors are required for retinogenesis, as well as patterning, differentiation and maintenance of specific retinal cell types. We hypothesized that Dlx1/Dlx2 and Brn3b homeobox ge...
Article
Full-text available
The incidence of heart failure with concomitant cardiac fibrosis is high worldwide.. In a phenoconversion event, which is causal to cardiac fibrosis, normally quiescent cardiac fibroblasts become activated, hypersynthetic cardiac myofibroblasts. These cells directly contribute to the inappropriate remodelling of the myocardial interstitium, which l...
Article
The phenotype conversion of fibroblasts to myofibroblasts plays a key role in the pathogenesis of cardiac fibrosis. Numerous triggers of this conversion process have been identified, including plating of cells on solid substrates, cytokines such as transforming growth factor-β, and mechanical stretch; however, the underlying mechanisms remain incom...
Article
The phenotype conversion of fibroblasts to myofibroblasts plays a key role in the pathogenesis of cardiac fibrosis. Numerous triggers of this conversion process have been identified, including plating of cells on solid substrates, cytokines such as Transforming Growth Factor β, and mechanical stretch, however the underlying mechanisms remain incomp...
Article
Cardiac fibroblasts are the major extracellular matrix producing cells in the heart. Our laboratory was the first to demonstrate that the transcription factor scleraxis induces collagen 1α2 expression in both cardiac fibroblasts and myofibroblasts. Here we identify a novel post-translational mechanism by which scleraxis activity is regulated and de...
Article
In cardiac wound healing following myocardial infarction (MI), relatively inactive resident cardiac fibroblasts phenoconvert to hypersynthetic/secretory myofibroblasts that produce large quantities of extracellular matrix (ECM) and fibrillar collagen proteins. Our lab and others have identified TGFβ1 as being a persistent stimulus in the chronic an...
Article
Cardiac fibrosis is the pathological accumulation of cardiac extracellular matrix (ECM or matrix), which occurs in most types of heart disease. Major recent advances in our understanding have allowed us to identify cardiac fibrosis as a primary disease independent of either cardiomyocyte injury or loss. New developments within this field are burgeo...
Article
Cardiac fibroblasts synthesize and remodel the extracellular matrix (ECM) of the heart and are key players in the development of cardiac fibrosis. They are closely associated with cardiac development, function and disease. Cardiac fibroblasts exist as three distinct phenotypes: a non-contractile fibroblast, an intermediate phenotype called a protom...
Article
Background and Objective: Arterial stiffness is recognized as being an independent predictor of incipient vascular disease associated with obesity and metabolic syndrome. In obese subjects, the decrease in the plasma level of adiponectin, an anti-diabetic and anti-atherogenic adipokine, is well known. Hence the aim of our study was to examine the e...
Book
The unique biology of cardiac fibroblasts and related cells, such as cardiac myofibroblasts and valvular interstitial cells, distinguish them from other fibroblastic cells, a concept that is only beginning to be widely appreciated. Further, the natural signals that stimulate and inhibit cardiac fibrosis within these cells are not well understood. T...
Article
Homeobox genes are an evolutionarily conserved class of transcription factors that are critical for development of many organ systems, including the brain and eye. During retinogenesis, homeodomain-containing transcription factors, which are encoded by homeobox genes, play essential roles in the regionalization and patterning of the optic neuroepit...
Article
Full-text available
Fibroblast growth factor 2 (FGF-2) is a multifunctional protein synthesized as high (Hi-) and low (Lo-) molecular weight isoforms. Studies using rodent models showed that Hi- and Lo-FGF-2 exert distinct biological activities: after myocardial infarction, rat Lo-FGF-2, but not Hi-FGF-2, promoted sustained cardioprotection and angiogenesis, while Hi-...
Article
Full-text available
Background: Cardiac fibrosis is linked to fibroblast to myofibroblast phenoconversion and proliferation; mechanisms underlying this phenoconversion are poorly understood. c-Ski (Ski) is a negative regulator of TGF-β/Smad signaling in myofibroblasts, and may redirect the myofibroblast phenotype back to fibroblasts. Meox2 may alter TGF-β-mediated cel...
Article
The heart is the first organ to develop in order to supply the ever-increasing metabolic demands of the growing embryo. The heart is a unique structure in the body as it is derived from four distinct pools of progenitors: the first heart field (cardiac crescent), the second heart field (SHF), the proepicardial organ and the cardiac neural crest. Th...
Article
This review focuses on the role of adipokines in the maintenance of a healthy cardiovascular system, and the mechanisms by which these factors mediate the development of cardiovascular disease in obesity. Adipocytes are the major cell type comprising the adipose tissue. These cells secrete numerous factors, termed adipokines, into the blood, includ...
Data
The position or inclusion of the FLAG epitope does not affect MEOX2 function. Luciferase assay demonstrating the ability of N-terminal, C-terminal and non-FLAG tagged MEOX2 proteins to activate a 2272 bp p21CIP1/WAF1 promoter. * Indicates a statistically significant change (p<0.05) when compared to the empty vector controls. n.s. denotes no statist...
Data
Ectopic MEOX proteins are expressed at similar levels. N-terminally tagged MEOX proteins were detected using an anti-FLAG antibody and α-tubulin was used as a loading control. A) A representative western blot displaying the relative level of MEOX protein expression in HEK293 cells 24 hours after transfection. Each lane represents an independent tra...
Data
MEOX1 and MEOX2, but not MEOX2Q235E, bind to a region of the p21CIP1/WAF1 promoter. Electrophoretic mobility shift assays (EMSAs) were used to assess the DNA binding capabilities of the various MEOX proteins. The DNA probe contained two MEOX2 binding sites originating from the sequence −9519 bp to −9489 bp upstream of the p21CIP1/WAF1 transcription...
Data
List of PCR primers used to create MEOX1 and MEOX2 fusion proteins. (DOC)
Data
List of PCR primers used to create the p21CIP1/WAF1 promoter luciferase constructs. (DOC)
Data
List of PCR primers used for qRT-PCR. (DOC)
Data
Deletion of the HQ rich domain of MEOX2 does not alter protein expression, localization or function. A) Schematic representation of the MEOX2H68_Q85del protein compared to wild-type MEOX1 and MEOX2. B) A representative western blot demonstrating the subcellular localization of MEOX2 H68_Q85del protein compared to wild-type MEOX2 in HEK293 cells, 48...
Data
MEOX proteins bind to the proximal homeodomain binding site in the p16INK4a promoter. A) Overexposure of the p16INK4a EMSA shown in Figure 6B, left. Incubation of nuclear extracts from HUVECs infected with MEOX1 or MEOX2 with the Proximal probe resulted in the formation of distinct complexes (arrowhead) (left), indicating that both MEOX proteins ca...
Article
Full-text available
Senescence, the state of permanent cell cycle arrest, has been associated with endothelial cell dysfunction and atherosclerosis. The cyclin dependent kinase inhibitors p21(CIP1/WAF1) and p16(INK4a) govern the G(1)/S cell cycle checkpoint and are essential for determining whether a cell enters into an arrested state. The homeodomain transcription fa...
Chapter
The developing mesenchyme gives rise to a diverse host of important cell types, including fibroblasts, endothelial and smooth muscle cells. In postnatal tissues, stromal cells continue to differentiate into subtypes with specific functions, e.g., fibroblasts to myofibroblasts, but the molecular signals that govern their phenoconversion are incomple...
Article
Increased adrenergic drive is a major factor influencing the development of pathological cardiac hypertrophy, a stage which precedes overt heart failure. We examined the effect of resveratrol, a polyphenol (found predominantly in grapes), in preventing norepinephrine induced hypertrophy of adult cardiomyocyte, and the role of nitric oxide (NO) and...
Article
Conjugated linoleic acid (CLA) has been reported to reduce blood pressure in obese insulin-resistant rats, but its mechanism of action has not been identified. The objective of this study was to determine whether CLA isomers can reduce obesity-related hypertension in the fa/fa Zucker rat in relation to adiponectin production and endothelial nitric...
Article
The homeobox transcription factor PROX1 is essential for the development and maintenance of lymphatic vasculature. How PROX1 regulates lymphatic endothelial cell fate remains undefined. PROX1 has been shown to upregulate the expression of Cyclin E, which mediates the G(1) to S transition of the cell cycle. Here we demonstrate that PROX1 activates t...
Article
Cardiac hypertrophy is the compensatory enlargement of the heart aimed at reducing stress induced by either pressure overload or volume overload (VO); however, sustained hypertrophy leads to cardiac dysfunction. We hypothesize that cardiac dysfunction which develops due to VO will be associated with abnormalities in sarcoplasmic reticulum (SR) func...
Article
Full-text available
Although the modulation of ion channel gating by hormones and drugs has been extensively studied, much less is known about how cell surface ion channel expression levels are regulated. Here, we demonstrate that the cell surface density of both the heterologously expressed K+ channel encoded by the human ether-a-go-go-related gene (HERG) and its nat...
Article
Homeobox genes are an evolutionarily conserved class of transcription factors that are key regulators of developmental processes such as regional specification, patterning, migration and differentiation. In both mouse and humans, the developing forebrain is marked by distinct boundaries of homeobox gene expression at different developmental time po...
Article
Full-text available
Dlx homeobox genes are first expressed in embryonic retina at E11.5. The Dlx1/Dlx2 null retina has a reduced ganglion cell layer (GCL), with loss of late-born differentiated retinal ganglion cells (RGCs) due to increased apoptosis. TrkB signaling is proposed to regulate the dynamics of RGC apoptosis throughout development. DLX2 expression markedly...
Article
The ability to use molecular biology tools to down-regulate Na+/Ca2+ exchanger (NCX) expression will allow us to better understand the regulation of Ca(i)2+ and contractility in heart. Three different techniques to deplete NCX expression were compared: short hairpin RNA (shRNA), antisense RNA and exchanger inhibitory peptide expression via adenovir...
Article
Full-text available
Dlx homeobox genes play an important role in vertebrate forebrain development. Dlx1/Dlx2 null mice die at birth with an abnormal cortical phenotype, including impaired differentiation and migration of GABAergic interneurons to the neocortex. However, the molecular basis for these defects downstream of loss of Dlx1/Dlx2 function is unknown. Neuropil...
Article
During embryonic development, the cardiovascular system first forms and then gives rise to the lymphatic vascular system. Homeobox genes are essential for both the development of the blood and lymphatic vascular systems, as well as for their maintenance in the adult. These genes all encode proteins that are transcription factors that contain a well...
Article
Full-text available
Dietary flaxseed has significant anti-atherogenic effects. However, the limits of this action and its effects on vascular contractile function are not known. We evaluated the effects of flaxseed supplementation on atherosclerosis and vascular function under prolonged hypercholesterolemic conditions in New Zealand White rabbits assigned to one of fo...
Article
Many commonly used medications can cause long QT syndrome and thus increase the risk of life-threatening arrhythmias. High-affinity human Ether-à-go-go-related gene (HERG) potassium channel blockade by structurally diverse compounds is almost exclusively responsible for this side effect. Understanding drug-HERG channel interactions is an important...
Article
The molecular mechanisms by which Mesenchyme Homeobox 2 (Meox2) regulates the proliferation, differentiation and migration of vascular smooth muscle cells and cardiomyocytes are not known. The discovery of MEOX2 binding proteins will aid in understanding how MEOX2 functions as a regulator of these key cellular processes. To identify MEOX2 binding p...
Article
Full-text available
Sarcolemmal-membrane-associated proteins (SLMAPs) define a new class of coiled-coil tail-anchored membrane proteins generated by alternative splicing mechanisms. An in vivo expression analysis indicated that SLMAPs are present in somites (11 days post-coitum) as well as in fusing myotubes and reside at the level of the sarcoplasmic reticulum and tr...
Article
Full-text available
The process of angiogenesis has been well documented, but little is known about the biology of lymphatic endothelial cells and the molecular mechanisms controlling lymphangiogenesis. The homeobox gene Prox1 is expressed in a subpopulation of endothelial cells that, after budding from veins, gives rise to the mammalian lymphatic system. In Prox1(-)(...
Article
Full-text available
Novel splice variants of the alpha(1) subunit of the Ca(v)1.2 voltage-gated Ca(2+) channel were identified that predicted two truncated forms of the alpha(1) subunit comprising domains I and II generated by alternative splicing in the intracellular loop region linking domains II and III. In rabbit heart splice variant 1 (RH-1), exon 19 was deleted,...
Article
Full-text available
The sarcolemmal associated proteins (SLAPs) are encoded by multiple mRNAs that are presumably generated by alternative splicing mechanisms. The amino acid sequence of the SLAP1 isoform exhibited 76% identity with TOPAP, a topographically graded antigen of the chick visual system. The regions of coiled-coil structure including an 11-heptad acidic am...
Article
Several genes are required during the early phases of liver specification, proliferation and differentiation. Here we report that Prox1 is required for hepatocyte migration. Loss of Prox1 leads to formation of a smaller liver with a reduced population of clustered hepatocytes surrounded by a laminin-rich basal membrane.