Neeta Adhikari

University of Minnesota Twin Cities | UMN · Division of Cardiology

Introduction: Cardiac fibrosis, characterized by wall stiffening, reduced contractility, and impaired overall heart performance, is a self-reinforcing process in response to injury (e.g., myocardial infarction) and pressure overload (e.g., systemic hypertension and pulmonary arterial hypertension [PAH]). The severity of cardiac fibrosis is associa...

Introduction Mitochondrial Ca ²⁺ (mtCa ²⁺ ) uptake via a main mtCa ²⁺ channel, mtCa ²⁺ uniporter (MCU), mediates cell survival and death via its contribution of mitochondrial ATP synthesis and apoptotic signaling activation, respectively. Our group previously showed that G q protein–coupled receptor (G q PCR) stimulation promotes activation of a ty...

Metabolic syndrome contributes to cardiovascular disease partly through systemic risk factors. However, local processes in the artery wall are becoming increasingly recognized to exacerbate atherosclerosis both in mice and humans. We show that arterial smooth muscle cell (SMC) glucose metabolism markedly synergizes with metabolic syndrome in accele...

Bromodomain-containing protein dysregulation is linked to cancer, diabetes, and inflammation. Selec-tive inhibition of bromodomain function is a newly proposed therapeutic strategy. We describe a 19F NMR dual screening method for small molecule discovery using fluorinated tryptophan resonances on two bromodomain-containing proteins. The chemical sh...

Vascular smooth muscle cells (VSMCs) play important roles in cardiovascular disorders and biology. Outlined in this paper is a step-by-step procedure for isolating aortic VSMCs from adult C57BL6J male mice by enzymatic digestion of the aorta using collagenase. The plating, culturing, and subculturing of the isolated cells are discussed in detail al...

Background – Genome wide association studies (GWAS) are powerful tools for nominating pathogenic variants, but offer little insight as to how candidate genes impact disease outcome. Such is the case for SH2B adaptor protein 3 (SH2B3), which is a negative regulator of multiple cytokine signaling pathways and is associated with increased risk of myoc...

Atherosclerosis, a syndrome with abnormal arterial walls, is one of the major causes that lead to the development of various cardiovascular diseases. The key initiator of atherosclerosis is cholesterol accumulation. The uncontrolled cholesterol deposition, mainly involving low-density lipoprotein (LDL), causes atheroma plaque formation, which initi...

Rationale The rationale was to utilize a bioinformatics approach to identify miRNA binding sites in genes with single nucleotide mutations (SNPs) to discover pathways in heart failure (HF). Objective The objective was to focus on the genes containing miRNA binding sites with miRNAs that were significantly altered in end-stage HF and in response to...

Background: Genome wide association studies (GWAS) are powerful tools for nominating pathogenic variants, but offer little insight as to how candidate genes impact disease outcome. Such is the case for SH2B adaptor protein 3 (SH2B3), which is associated with coronary artery disease (CAD), atherosclerosis, and risk of myocardial infarction (MI), but...

. Members of the miR-16 family are up-regulated during ischemia and heart failure. The goal of these studies was to identify novel miR-16 mediated signaling pathways that may play a role in cardiovascular disease. We used bioinformatics to identify single nucleotide polymorphisms (SNPs) in binding sites of miR-16 using dbSNP and the exome sequencin...

Continuous-flow left ventricular assist devices (LVADs) are an established therapy for patients with end-stage heart failure. The short- and long-term impact of these devices on peripheral blood gene expression has not been characterized, and may provide insight into the molecular pathways mediated in response to left ventricular remodeling and an...

Heparan sulfate proteoglycans act as co-receptors for many chemokines and growth factors. The sulfation pattern of the heparan sulfate chains is a critical regulatory step affecting the binding of chemokines and growth factors. N-deacetylase-N-sulfotransferase1 (Ndst1) is one of the first enzymes to catalyze sulfation. Previously published work has...

Purpose: The overall success of modern left ventricular assist devices (LVADs) has been mitigated by the complication of gastrointestinal (GI) bleeding. While evidence suggests that anticoagulation and acquired von Willebrand factor deficiency contribute, these two factors do not fully explain all bleeding events. Methods and Materials: To identify...

Heparan sulfate proteoglycans are abundant matrix and membrane molecules. Smooth muscle specific deletion of one heparan sulfate biosynthetic enzyme, N-deacetylase-N-sulfotransferase1 leads to decreased vascular smooth muscle cell proliferation, and vascular wall thickness. We hypothesized that this may lead to changes in blood pressure in consciou...

MicroRNAs are a class of small non-coding RNAs that regulate gene expression by binding to discrete sites of genes and inhibiting translation. The objective of this study was to identify microRNAs and downstream enriched targets associated with symptomatic carotid plaques. Carotid plaque samples from patients were defined as symptomatic if they wer...

Proteoglycan core proteins are linked to four different classes of linear sugar chains referred to as glycosaminoglycans. Heparan sulfate constitutes one of these classes of glycosaminoglycans, and has been shown to be important in developmental processes as well as disease. We designed a low-density gene expression array to identify expression lev...

The goal of this study was to test the contributing role of increasing glucose uptake in vascular smooth muscle cells (VSMCs) in vascular complications and disease. A murine genetic model was established in which glucose trasporter 1 (GLUT1), the non-insulin-dependent glucose transporter protein, was overexpressed in smooth muscle using the sm22α p...

Adaptive changes to oxygen availability are critical for cell survival and tissue homeostasis. Prolonged oxygen deprivation due to reduced blood flow to cardiac or peripheral tissues can lead to myocardial infarction and peripheral vascular disease, respectively. Mammalian cells respond to hypoxia by modulating oxygen-sensing transducers that stabi...

Sprouty1 (Spry1) is a conserved antagonist of FGF signaling. The goal of this study was to further explore the downstream mechanisms governing Spry1 inhibition of endothelial cell proliferation. Up-regulation of Spry1 in HUVECs inhibited tube formation on Matrigel (n = 6, P < 0.001). This was associated with decreased proliferation as measured by B...

The mitogen activated protein kinase (MAPK) signaling pathway regulates multiple events leading to heart failure including ventricular remodeling, contractility, hypertrophy, apoptosis, and fibrosis. The regulation of conserved intrinsic inhibitors of this pathway is poorly understood. We recently identified an up-regulation of Sprouty1 (Spry1) in...

Heparan sulfate proteoglycans are abundant molecules in the extracellular matrix and at the cell surface. Heparan sulfate chains are composed of groups of disaccharides whose side chains are modified through a series of enzymatic reactions. Deletion of these enzymes alters heparan sulfate fine structure and leads to changes in cell proliferation an...

Common variants in the transcription factor 7-like 2 (TCF7L2) gene have been identified as the strongest genetic risk factors for type 2 diabetes (T2D). However, the mechanisms by which these non-coding variants increase risk for T2D are not well-established. We used 13 expression assays to survey mRNA expression of multiple TCF7L2 splicing forms i...

The purpose of this study was to determine the effects of chronic treatment with the beta 2 adrenergic receptor agonist clenbuterol on endothelial progenitor cells (EPC) in a well-characterized model of heart failure, the muscle LIM protein knockout (MLP(-/-)) mouse. MLP(-/-) mice were treated daily with clenbuterol (2 mg/kg) or saline subcutaneous...

Heparan sulfate (HS) is ubiquitous throughout the human body. The backbone of HS is composed of many types of sugars. HS serves as a docking site for a vast array of protein ligands. Recent evidence suggests a unique diversity in HS structure that alters protein binding and protein function. This diversity in HS structure has been overlooked till n...

Redox factor-1 (Ref-1) is a multifunctional protein that regulates redox, DNA repair, and the response to cell stress. We previously demonstrated that Ref-1(+/-) mice exhibit a significantly reduced Ref-1 mRNA and protein levels within the vasculature, which are associated with increased oxidative stress. The goal of this study was to test the hypo...

Our understanding of the molecular signaling pathways regulating the initiation and progression of atherosclerosis or remodeling in response to injury has begun to cross the boundaries from regulation of well-described canonical pathways to the interplay between these pathways. The focus of this review is to summarize our current understanding of a...

Given the well-defined role of LIM-motif containing proteins in cytoskeletal organization, cell fate, and differentiation, we hypothesized that the regulation of LIM proteins played an integral role in vascular remodeling. We screened a compendium of cDNA microarray data from rat vascular smooth muscle cells (VSMC) for novel LIM-containing targets...

Initial studies have established expression of low-density lipoprotein (LDL) receptor-related protein 6 (LRP6) in vascular smooth muscle cells (VSMCs). We hypothesized that LRP6 is a critical mediator governing the regulation of the canonical Wnt/beta-catenin/T cell factor 4 (Tcf-4) cascade in the vasculature. This hypothesis was based on our previ...

We screened a compendium of gene profiles from 19 paired human heart samples harvested at the time of implant and explant of a left ventricular assist device (LVAD) for novel genes regulating the Ras/MEK/ERK cascade. From this analysis we identified Sprouty1, an evolutionally conserved gene that acts as an intrinsic inhibitor of the Ras/MEK/ERK pat...

Degradation of IkappaB is an essential step in nuclear factor (NF)-kappaB activation. However, the determinants regulating this process have not been defined in vascular smooth muscle cells (VSMCs). We hypothesized that the E3-ligase, beta-transducin repeat-containing protein 1 (beta-TrCP1), was a rate-determining mediator that regulates the ubiqui...

Lead is a well-documented testicular toxicant. The present work was planned to study the occurrence of germ cell death after lead administration. Young growing rats were treated with 5, 10 and 20 mg kg−1 body weight of lead for 2 weeks. Cell death was assessed by employing in situ TUNEL staining, DNA electrophoresis and morphological examination of...

In vivo sister chromatid exchange (SCE) and chromosome aberrations (CA) were carried out for six salicylic acid derivatives in bone marrow cells of mice. Six salicylic acid derivatives, namely acetyl salicylic acid (aspirin), salicylic acid, salicylamide, sodium salicylate, diflunisal and niclosamide, were used for these experiments. Drugs were adm...

The genotoxic effects of five pesticides (benomyl, 2,4-D, dimecron, monocrotophos, and vitavax) were evaluated in the rat bone marrow cytogenetic assay. The spectrum of aberrations observed included chromatid breaks, chromatid fragments, ring chromosomes, dicentric chromosomes, and chromosome fragments. It was observed that 2,4-D, dimecron, and vit...