Publications by authors named "Joseph I Shapiro"

166 Publications

The Na/K-ATPase α1/Src interaction regulates metabolic reserve and Western diet intolerance.

Acta Physiol (Oxf) 2021 Mar 22:e13652. Epub 2021 Mar 22.

Marshall Institute for Interdisciplinary Research, Marshall University, Huntington, WV, USA.

Aim: Highly prevalent diseases such as insulin resistance and heart failure are characterized by reduced metabolic flexibility and reserve. We tested whether Na/K-ATPase (NKA)-mediated regulation of Src kinase, which requires two NKA sequences specific to the α1 isoform, is a regulator of metabolic capacity that can be targeted pharmacologically.

Methods: Metabolic capacity was challenged functionally by Seahorse metabolic flux analyses and glucose deprivation in LLC-PK1-derived cells expressing Src binding rat NKA α1, non-Src-binding rat NKA α2 (the most abundant NKA isoform in the skeletal muscle), and Src binding gain-of-function mutant rat NKA α2. Mice with skeletal muscle-specific ablation of NKA α1 (skα1-/-) were generated using a MyoD:Cre-Lox approach and were subjected to treadmill testing and Western diet. C57/Bl6 mice were subjected to Western diet with or without pharmacological inhibition of NKA α1/Src modulation by treatment with pNaKtide, a cell-permeable peptide designed by mapping one of the sites of NKA α1/Src interaction.

Results: Metabolic studies in mutant cell lines revealed that the Src binding regions of NKA α1 are required to maintain metabolic reserve and flexibility. Skα1-/- mice had decreased exercise endurance and mitochondrial Complex I dysfunction. However, skα1-/- mice were resistant to Western diet-induced insulin resistance and glucose intolerance, a protection phenocopied by pharmacological inhibition of NKA α1-mediated Src regulation with pNaKtide.

Conclusions: These results suggest that NKA α1/Src regulatory function may be targeted in metabolic diseases. Because Src regulatory capability by NKA α1 is exclusive to endotherms, it may link the aerobic scope hypothesis of endothermy evolution to metabolic dysfunction.
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http://dx.doi.org/10.1111/apha.13652DOI Listing
March 2021

Biased Effect of Cardiotonic Steroids on Na/K-ATPase-Mediated Signal Transduction.

Mol Pharmacol 2021 03 25;99(3):217-225. Epub 2021 Jan 25.

Marshall Institute for Interdisciplinary Research, Huntington, West Virginia (Y.X., P.M., M.H., T.W., L.C., Z.X.); University of Toledo College of Medicine and Life Sciences, Toledo, Ohio (J.X.X.); Joan C. Edwards School of Medicine at Marshall University, Huntington, West Virginia (J.I.S.); and Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing, P. R. China, and Jiangsu Food and Pharmaceutical Science College, Huai'an, P. R. China (F.F.).

Recent studies have revealed that Na/K-ATPase (NKA) can transmit signals through ion-pumping-independent activation of pathways relayed by distinct intracellular protein/lipid kinases, and endocytosis challenges the traditional definition that cardiotonic steroids (CTS) are NKA inhibitors. Although additional effects of CTS have long been suspected, revealing its agonist impact through the NKA receptor could be a novel mechanism in understanding the basic biology of NKA. In this study, we tested whether different structural CTS could trigger different sets of NKA/effector interactions, resulting in biased signaling responses without compromising ion-pumping capacity. Using purified NKA, we found that ouabain, digitoxigenin, and somalin cause comparable levels of NKA inhibition. However, although endogenous ouabain stimulates both protein kinases and NKA endocytosis, digitoxigenin and somalin bias to protein kinases and endocytosis, respectively, in LLC-PK1 cells. The positive inotropic effects of CTS are traditionally regarded as NKA inhibitors. However, CTS-induced signaling occurs at concentrations at least one order of magnitude lower than that of inotropy, which eliminates their well known toxic actions on the heart. The current study adds a novel mechanism that CTS could exert its biased signaling properties through the NKA signal transducer. SIGNIFICANCE STATEMENT: Although it is now well accepted that NKA has an ion-pumping-independent signaling function, it is still debated whether direct and conformation-dependent NKA/effector interaction is a key to this function. Therefore, this investigation is significant in advancing our understanding of the basic biology of NKA-mediated signal transduction and gaining molecular insight into the structural elements that are important for cardiotonic steroid's biased action.
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http://dx.doi.org/10.1124/molpharm.120.000101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7919863PMC
March 2021

The potential role of Na-K-ATPase and its signaling in the development of anemia in chronic kidney disease.

Am J Physiol Renal Physiol 2021 02 28;320(2):F234-F242. Epub 2020 Dec 28.

Department of Medicine, Joan C. Edwards School of Medicine, Marshall University, Huntington, West Virginia.

Chronic kidney disease (CKD) is one of the most prominent diseases affecting our population today. According to the Factsheet published by Centers for Disease Control and Prevention (CDC), it effects approximately 15% of the total population in the United States in some way, shape, or form. Within the myriad of symptomatology associated with CKD, one of the most prevalent factors in terms of affecting quality of life is anemia. Anemia of CKD cannot be completely attributed to one mechanism or cause, but rather has a multifactorial origin in the pathophysiology of CKD. While briefly summarizing well-documented risk factors, this review, as a hypothesis, aims to explore the possible role of Na-K-ATPase and its signaling function [especially recent identified reactive oxygen species (ROS) amplification function] in the interwoven mechanisms of development of the anemia of CKD.
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http://dx.doi.org/10.1152/ajprenal.00244.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7948124PMC
February 2021

A strategic expression method of miR-29b and its anti-fibrotic effect based on RNA-sequencing analysis.

PLoS One 2020 17;15(12):e0244065. Epub 2020 Dec 17.

Joan C. Edwards School of Medicine, Department of Biomedical Sciences, Marshall University, Huntington, West Virginia, United States of America.

Tissue fibrosis is a significant health issue associated with organ dysfunction and failure. Increased deposition of collagen and other extracellular matrix (ECM) proteins in the interstitial area is a major process in tissue fibrosis. The microRNA-29 (miR-29) family has been demonstrated as anti-fibrotic microRNAs. Our recent work showed that dysregulation of miR-29 contributes to the formation of cardiac fibrosis in animal models of uremic cardiomyopathy, whereas replenishing miR-29 attenuated cardiac fibrosis in these animals. However, excessive overexpression of miR-29 is a concern because microRNAs usually have multiple targets, which could result in unknown and unexpected side effect. In the current study, we constructed a novel Col1a1-miR-29b vector using collagen 1a1 (Col1a1) promoter, which can strategically express miR-29b-3p (miR-29b) in response to increased collagen synthesis and reach a dynamic balance between collagen and miR-29b. Our experimental results showed that in mouse embryonic fibroblasts (MEF cells) transfected with Col1a1-miR-29b vector, the miR-29b expression is about 1000 times less than that in cells transfected with CMV-miR-29b vector, which uses cytomegalovirus (CMV) as a promoter for miR-29b expression. Moreover, TGF-β treatment increased the miR-29b expression by about 20 times in cells transfected with Col1a1-miR-29b, suggesting a dynamic response to fibrotic stimulation. Western blot using cell lysates and culture media demonstrated that transfection of Col1a1-miR-29b vector significantly reduced TGF-β induced collagen synthesis and secretion, and the effect was as effective as the CMV-miR-29b vector. Using RNA-sequencing analysis, we found that 249 genes were significantly altered (180 upregulated and 69 downregulated, at least 2-fold change and adjusted p-value <0.05) after TGF-β treatment in MEF cells transfected with empty vector. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis using GAGE R-package showed that the top 5 upregulated pathways after TGF-β treatment were mostly fibrosis-related, including focal adhesion, ECM reaction, and TGF-β signaling pathways. As expected, transfection of Col1a1-miR-29b or CMV-miR-29b vector partially reversed the activation of these pathways. We also analyzed the expression pattern of the top 100 miR-29b targeting genes in these cells using the RNA-sequencing data. We identified that miR-29b targeted a broad spectrum of ECM genes, but the inhibition effect is mostly moderate. In summary, our work demonstrated that the Col1a1-miR-29b vector can be used as a dynamic regulator of collagen and other ECM protein expression in response to fibrotic stimulation, which could potentially reduce unnecessary side effect due to excessive miR-29b levels while remaining an effective potential therapeutic approach for fibrosis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0244065PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7746150PMC
March 2021

Stress Signal Regulation by Na/K-ATPase As a New Approach to Promote Physiological Revascularization in a Mouse Model of Ischemic Retinopathy.

Invest Ophthalmol Vis Sci 2020 12;61(14)

Marshall Institute for Interdisciplinary Research, Marshall University, Huntington, West Virginia, United States.

Purpose: The identification of target pathways to block excessive angiogenesis while simultaneously restoring physiological vasculature is an unmet goal in the therapeutic management of ischemic retinopathies. pNaKtide, a cell-permeable peptide that we have designed by mapping the site of α1 Na/K-ATPase (NKA)/Src binding, blocks the formation of α1 NKA/Src/reactive oxygen species (ROS) amplification loops and restores physiological ROS signaling in a number of oxidative disease models. The aim of this study was to evaluate the importance of the NKA/Src/ROS amplification loop and the effect of pNaKtide in experimental ischemic retinopathy.

Methods: Human retinal microvascular endothelial cells (HRMECs) and retinal pigment epithelium (ARPE-19) cells were used to evaluate the effect of pNaKtide on viability, proliferation, and angiogenesis. Retinal toxicity and distribution were assessed in those cells and in the mouse. Subsequently, the role and molecular mechanism of NKA/Src in ROS stress signaling were evaluated biochemically in the retinas of mice exposed to the well-established protocol of oxygen-induced retinopathy (OIR). Finally, pNaKtide efficacy was assessed in this model.

Results: The results suggest a key role of α1 NKA in the regulation of ROS stress and the Nrf2 pathway in mouse OIR retinas. Inhibition of α1 NKA/Src by pNaKtide reduced pathologic ROS signaling and restored normal expression of hypoxia-inducible factor 1-α/vascular endothelial growth factor (VEGF). Unlike anti-VEGF agents, pNaKtide did promote retinal revascularization while inhibiting neovascularization and inflammation.

Conclusions: Targeting α1 NKA represents a novel strategy to develop therapeutics that not only inhibit neovascularization but also promote physiological revascularization in ischemic eye diseases.
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http://dx.doi.org/10.1167/iovs.61.14.9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7718810PMC
December 2020

The Role of Histone Acetylation-/Methylation-Mediated Apoptotic Gene Regulation in Hepatocellular Carcinoma.

Int J Mol Sci 2020 Nov 24;21(23). Epub 2020 Nov 24.

Department of Surgery, Marshall University School of Medicine, Huntington, WV 25701, USA.

Epigenetics, an inheritable phenomenon, which influences the expression of gene without altering the DNA sequence, offers a new perspective on the pathogenesis of hepatocellular carcinoma (HCC). Nonalcoholic steatohepatitis (NASH) is projected to account for a significant share of HCC incidence due to the growing prevalence of various metabolic disorders. One of the major molecular mechanisms involved in epigenetic regulation, post-translational histone modification seems to coordinate various aspects of NASH which will further progress to HCC. Mounting evidence suggests that the orchestrated events of cellular and nuclear changes during apoptosis can be regulated by histone modifications. This review focuses on the current advances in the study of acetylation-/methylation-mediated histone modification in apoptosis and the implication of these epigenetic regulations in HCC. The reversibility of epigenetic alterations and the agents that can target these alterations offers novel therapeutic approaches and strategies for drug development. Further molecular mechanistic studies are required to enhance information governing these epigenetic modulators, which will facilitate the design of more effective diagnosis and treatment options.
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http://dx.doi.org/10.3390/ijms21238894DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7727670PMC
November 2020

Can charcoal improve outcomes in COVID-19 infections?

Med Hypotheses 2020 Nov 10;144:110176. Epub 2020 Aug 10.

Joan C. Edwards School of Medicine, Marshall University, United States. Electronic address:

COVID-19 infection causes considerable morbidity and mortality, especially to those who are aged, have impaired renal function and are obese. We propose to examine the potential utility of oral activated charcoal with the hypothesis that such treatment would lower absorption of microbiome derived toxins and ameliorate systemic oxidant stress and inflammation.
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http://dx.doi.org/10.1016/j.mehy.2020.110176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7416710PMC
November 2020

The Pivotal Role of Adipocyte-Na K peptide in Reversing Systemic Inflammation in Obesity and COVID-19 in the Development of Heart Failure.

Antioxidants (Basel) 2020 Nov 14;9(11). Epub 2020 Nov 14.

Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25755, USA.

This review summarizes data from several laboratories that have demonstrated a role of the Na/K-ATPase, specifically its α1 subunit, in the generation of reactive oxygen species (ROS) via the negative regulator of Src. Together with Src and other signaling proteins, the Na/K-ATPase forms an oxidant amplification loop (NKAL), amplifies ROS, and participates in cytokines storm in obesity. The development of a peptide fragment of the α1 subunit, NaKtide, has been shown to negatively regulate Src. Several groups showed that the systemic administration of the cell permeable modification of NaKtide (pNaKtide) or its selective delivery to fat tissue-adipocyte specific expression of NaKtide-ameliorate the systemic elevation of inflammatory cytokines seen in chronic obesity. Severe acute respiratory syndrome - coronavirus 2 (SARS-CoV-2), the RNA Coronavirus responsible for the COVID-19 global pandemic, invades cells via the angiotensin converting enzyme 2 (ACE-2) receptor (ACE2R) that is appended in inflamed fat tissue and exacerbates the formation of the cytokines storm. Both obesity and heart and renal failure are well known risks for adverse outcomes in patients infected with COVID-19. White adipocytes express ACE-2 receptors in high concentration, especially in obese patients. Once the virus invades the white adipocyte cell, it creates a COVID19-porphyrin complex which degrades and produces free porphyrin and iron and increases ROS. The increased formation of ROS and activation of the NKAL results in a further potentiated formation of ROS production, and ultimately, adipocyte generation of more inflammatory mediators, leading to systemic cytokines storm and heart failure. Moreover, chronic obesity also results in the reduction of antioxidant genes such as heme oxygenase-1 (HO-1), increasing adipocyte susceptibility to ROS and cytokines. It is the systemic inflammation and cytokine storm which is responsible for many of the adverse outcomes seen with COVID-19 infections in obese subjects, leading to heart failure and death. This review will also describe the potential antioxidant drugs and role of NaKtide and their demonstrated antioxidant effect used as a major strategy for improving obesity and epicardial fat mediated heart failure in the context of the COVID pandemic.
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http://dx.doi.org/10.3390/antiox9111129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7697697PMC
November 2020

Author Correction: The Adipocyte Na/K-ATPase Oxidant Amplification Loop is the Central Regulator of Western Diet-Induced Obesity and Associated Comorbidities.

Sci Rep 2020 Nov 5;10(1):19561. Epub 2020 Nov 5.

Departments of Medicine, Surgery, Biomedical Sciences, and Healthcare Informatics Program, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, USA.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41598-020-75948-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7645717PMC
November 2020

Response to: Visaria et al. Everything in moderation: Understanding the interplay between salt and sugar intake.

J Clin Hypertens (Greenwich) 2020 12 30;22(12):2387-2388. Epub 2020 Oct 30.

Internal Medicine Department, Marshall University Joan C. Edwards School of Medicine, Huntington, West Virginia, USA.

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http://dx.doi.org/10.1111/jch.14085DOI Listing
December 2020

Therapeutic Efficacy of Antioxidants in Ameliorating Obesity Phenotype and Associated Comorbidities.

Front Pharmacol 2020 13;11:1234. Epub 2020 Aug 13.

Departments of Medicine, Surgery and Biomedical Sciences, Marshall University Joan C. Edwards School of Medicine, Huntington, WV, United States.

Obesity has been a worldwide epidemic for decades. Despite the abundant increase in knowledge regarding the etiology and pathogenesis of obesity, the prevalence continues to rise with estimates predicting considerably higher numbers by the year 2030. Obesity is characterized by an abnormal lipid accumulation, however, the physiological consequences of obesity are far more concerning. The development of the obesity phenotype constitutes dramatic alterations in adipocytes, along with several other cellular mechanisms which causes substantial increase in systemic oxidative stress mediated by reactive oxygen species (ROS). These alterations promote a chronic state of inflammation in the body caused by the redox imbalance. Together, the systemic oxidative stress and chronic inflammation plays a vital role in maintaining the obese state and exacerbating onset of cardiovascular complications, Type II diabetes mellitus, dyslipidemia, non-alcoholic steatohepatitis, and other conditions where obesity has been linked as a significant risk factor. Because of the apparent role of oxidative stress in the pathogenesis of obesity, there has been a growing interest in attenuating the pro-oxidant state in obesity. Hence, this review aims to highlight the therapeutic role of antioxidants, agents that negate pro-oxidant state of cells, in ameliorating obesity and associated comorbidities. More specifically, this review will explore how various antioxidants target unique and diverse pathways to exhibit an antioxidant defense mechanism.
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http://dx.doi.org/10.3389/fphar.2020.01234DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7438597PMC
August 2020

Oxidant-Induced Alterations in the Adipocyte Transcriptome: Role of the Na,K-ATPase Oxidant Amplification Loop.

Int J Mol Sci 2020 Aug 18;21(16). Epub 2020 Aug 18.

Departments of Medicine, Surgery, and Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25755, USA.

(1) Background: Recently we have noted that adipocyte specific expression of the peptide, NaKtide, which was developed to attenuate the Na,K-ATPase oxidant amplification loop, could ameliorate the phenotypical features of uremic cardiomyopathy. We performed this study to better characterize the cellular transcriptomes that are involved in various biological pathways associated with adipocyte function occurring with renal failure. (2) Methods: RNAseq was performed on the visceral adipose tissue of animals subjected to partial nephrectomy. Specific expression of NaKtide in adipocytes was achieved using an adiponectin promoter. To better understand the cause of gene expression changes in vivo, 3T3L1 adipocytes were exposed to indoxyl sulfate (IS) or oxidized low density lipoprotein (oxLDL), with and without pNaKtide (the cell permeant form of NaKtide). RNAseq was also performed on these samples. (3) Results: We noted a large number of adipocyte genes were altered in experimental renal failure. Adipocyte specific NaKtide expression reversed most of these abnormalities. High correlation with some cardiac specific phenotypical features was noted amongst groups of these genes. In the murine adipocytes, both IS and oxLDL induced similar pathway changes as were noted in vivo, and pNaKtide appeared to reverse these changes. Network analysis demonstrated tremendous similarities between the network revealed by gene expression analysis with IS compared with oxLDL, and the combined in vitro dataset was noted to also have considerable similarity to that seen in vivo with experimental renal failure. (4) Conclusions: This study suggests that the myriad of phenotypical features seen with experimental renal failure may be fundamentally linked to oxidant stress within adipocytes.
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http://dx.doi.org/10.3390/ijms21165923DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7460641PMC
August 2020

Relationship between dietary sodium and sugar intake: A cross-sectional study of the National Health and Nutrition Examination Survey 2001-2016.

J Clin Hypertens (Greenwich) 2020 09 6;22(9):1694-1702. Epub 2020 Aug 6.

Internal Medicine Department, Marshall University Joan C. Edwards School of Medicine, Huntington, West Virginia, USA.

Dietary sodium intake and cardiovascular outcomes have a reported J-shaped curve relationship. This study analyzes the relationship between dietary sodium and sugar intake as a potential mechanism to explain this association. The authors examined cross-sectional data from the National Health and Nutrition Examination Survey (NHANES) 2001-2016 where dietary sodium, carbohydrate, fat, cholesterol, and sugar intakes were assessed by 24-hour dietary recall and were standardized to a total daily intake of 2000 calories. Sodium intake was categorized into sodium quintiles (SQ) as follows: SQ1(0.06-2.6 g/d); SQ2(2.6-3.0 g/d); SQ3(3.0-3.4 g/d); SQ4(3.4-4.0 g/d); and SQ5(4.0-29.3 g/d). Simple and multivariate linear regression using SQ3 as reference were used to assess associations between daily sodium intake and the other nutrients. Our results showed that among 38 722 participants that met our study criteria, the mean age was 43.6 years (SD 16.8 years) and sex was equally distributed (48.8% male vs 51.2% female). Sugar intake went down across increasing SQs and was significantly higher in SQ1 (141.2 g/d) and SQ2 (118.6 g/d) and significantly lower in SQ4 (97.9 g/d) and SQ5 (85.6 g/d) compared to SQ3 (108.6 g/d; all P < .01). These same trends remained unchanged and significant in the fully adjusted multivariate model. In conclusion, NHANES study participants reporting low sodium intake on 24-hour dietary recall have a higher consumption of sugar. The negative impact of low sodium diet on cardiovascular health may be explained at least partially by the associated high sugar intake.
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http://dx.doi.org/10.1111/jch.13985DOI Listing
September 2020

Genetic Polymorphisms Complicate COVID-19 Therapy: Pivotal Role of HO-1 in Cytokine Storm.

Antioxidants (Basel) 2020 Jul 18;9(7). Epub 2020 Jul 18.

Department of Pharmacology, New York Medical College, Valhalla, NY 10595, USA.

Coronaviruses are very large RNA viruses that originate in animal reservoirs and include severe acute respiratory distress syndrome (SARS) and Middle East respiratory syndrome (MERS) and other inconsequential coronaviruses from human reservoirs like the common cold. SARS-CoV-2, the virus that causes COVID-19 and is believed to originate from bat, quickly spread into a global pandemic. This RNA virus has a special affinity for porphyrins. It invades the cell at the angiotensin converting enzyme-2 (ACE-2) receptor and binds to hemoproteins, resulting in a severe systemic inflammatory response, particularly in high ACE-2 organs like the lungs, heart, and kidney, resulting in systemic disease. The inflammatory response manifested by increased cytokine levels and reactive oxygen species results in inhibition of heme oxygenase (HO-1), with a subsequent loss of cytoprotection. This has been seen in other viral illness like human immunodeficiency virus (HIV), Ebola, and SARS/MERS. There are a number of medications that have been tried with some showing early clinical promise. This illness disproportionately affects patients with obesity, a chronic inflammatory disease with a baseline excess of cytokines. The majority of the medications used in the treatment of COVID-19 are metabolized by cytochrome P450 (CYP) enzymes, primarily CYP2D6. This is further complicated by genetic polymorphisms of CYP2D6, HO-1, ACE, and ACE-2. There is a potential role for HO-1 upregulation to treat/prevent cytokine storm. Current therapy must focus on antivirals and heme oxygenase upregulation. Vaccine development will be the only magic bullet.
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http://dx.doi.org/10.3390/antiox9070636DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7402116PMC
July 2020

Central Role for Adipocyte Na,K-ATPase Oxidant Amplification Loop in the Pathogenesis of Experimental Uremic Cardiomyopathy.

J Am Soc Nephrol 2020 08 25;31(8):1746-1760. Epub 2020 Jun 25.

Departments of Medicine, Surgery, and Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, West Virginia

Background: Oxidative stress in adipocyte plays a central role in the pathogenesis of obesity as well as in the associated cardiovascular complications. The putative uremic toxin indoxyl sulfate induces oxidative stress and dramatically alters adipocyte phenotype . Mice that have undergone partial nephrectomy serve as an experimental model of uremic cardiomyopathy. This study examined the effects on adipocytes of administering a peptide that reduces oxidative stress to the mouse model.

Methods: A lentivirus vector introduced the peptide NaKtide with an adiponectin promoter into the mouse model of experimental uremic cardiomyopathy, intraperitoneally. Then adipocyte-specific expression of the peptide was assessed for mice fed a standard diet compared with mice fed a western diet enriched in fat and fructose.

Results: Partial nephrectomy induced cardiomyopathy and anemia in the mice, introducing oxidant stress and an altered molecular phenotype of adipocytes that increased production of systemic inflammatory cytokines instead of accumulating lipids, within 4 weeks. Consumption of a western diet significantly worsened the adipocyte oxidant stress, but expression of NaKtide in adipocytes completely prevented the worsening. The peptide-carrying lentivirus achieved comparable expression in skeletal muscle, but did not ameliorate the disease phenotype.

Conclusions: Adipocyte-specific expression of NaKtide, introduced with a lentiviral vector, significantly ameliorated adipocyte dysfunction and uremic cardiomyopathy in partially nephrectomized mice. These data suggest that the redox state of adipocytes controls the development of uremic cardiomyopathy in mice subjected to partial nephrectomy. If confirmed in humans, the oxidative state of adipocytes may be a therapeutic target in chronic renal failure.
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http://dx.doi.org/10.1681/ASN.2019101070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7460907PMC
August 2020

A caveolin binding motif in Na/K-ATPase is required for stem cell differentiation and organogenesis in mammals and .

Sci Adv 2020 May 27;6(22):eaaw5851. Epub 2020 May 27.

Marshall Institute for Interdisciplinary Research (MIIR) at Marshall University, Huntington, WV, USA.

Several signaling events have been recognized as essential for regulating cell lineage specification and organogenesis in animals. We find that the gain of an amino-terminal caveolin binding motif (CBM) in the α subunit of the Na/K-adenosine triphosphatase (ATPase) (NKA) is required for the early stages of organogenesis in both mice and . The evolutionary gain of the CBM occurred at the same time as the acquisition of the binding sites for Na/K. Loss of this CBM does not affect cell lineage specification or the initiation of organogenesis, but arrests further organ development. Mechanistically, this CBM is essential for the dynamic operation of Wnt and the timely up-regulation of transcriptional factors during organogenesis. These results indicate that the NKA was evolved as a dual functional protein that works in concert with Wnt as a hitherto unrecognized common mechanism to enable stem cell differentiation and organogenesis in multicellular organisms within the animal kingdom.
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http://dx.doi.org/10.1126/sciadv.aaw5851DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7253156PMC
May 2020

The Na/K-ATPase α1 and c-Src form signaling complex under native condition: A crosslinking approach.

Sci Rep 2020 04 7;10(1):6006. Epub 2020 Apr 7.

Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, 25755, USA.

The protein-protein interactions amongst the Na/K-ATPase α1 subunit, c-Src, and caveolin-1 (cav-1) are essential for the Na/K-ATPase signaling functions. However, there are arguments concerning the interaction model. The present study aims to clarify the interactions amongst the endogenous native proteins in live cells under native resting condition. Under native condition, Blue Native-PAGE and Blue Native-PAGE/SDS-PAGE 2D analyses demonstrated co-existence of the α1 subunit and c-Src in same protein complex, as well as a direct interaction between the α1 subunit and c-Src. By comparison of cleavable and non-cleavable cysteine-cysteine crosslinked samples, capillary immunoblotting analysis demonstrated that depletion of Src kinase family members (c-Src, Yes, and Fyn) or cav-1 clearly reduced the interactions of the α1 subunit with proteins, but depletion of cav-1 did not affect the interaction of c-Src with the α1 subunit. The data indicated that there are direct interactions between the α1 subunit and c-Src as well as between the α1 subunit and cav-1, but argued about the interaction between c-Src and cav-1 under the condition. Furthermore, the data also indicated the existence of different protein complexes containing the α1 subunit and c-Src, which might have different signaling functions.
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http://dx.doi.org/10.1038/s41598-020-61920-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7138855PMC
April 2020

The Redox-Sensitive Na/K-ATPase Signaling in Uremic Cardiomyopathy.

Int J Mol Sci 2020 Feb 13;21(4). Epub 2020 Feb 13.

Department of Medicine, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25755, USA.

In recent years, Na/K-ATPase signaling has been implicated in different physiological and pathophysiological conditions, including cardiac hypertrophy and uremic cardiomyopathy. Cardiotonic steroids (CTS), specific ligands of Na/K-ATPase, regulate its enzymatic activity (at higher concentrations) and signaling function (at lower concentrations without significantly affecting its enzymatic activity) and increase reactive oxygen species (ROS) generation. On the other hand, an increase in ROS alone also regulates the Na/K-ATPase enzymatic activity and signaling function. We termed this phenomenon the Na/K-ATPase-mediated oxidant-amplification loop, in which oxidative stress regulates both the Na/K-ATPase activity and signaling. Most recently, we also demonstrated that this amplification loop is involved in the development of uremic cardiomyopathy. This review aims to evaluate the redox-sensitive Na/K-ATPase-mediated oxidant amplification loop and uremic cardiomyopathy.
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http://dx.doi.org/10.3390/ijms21041256DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072896PMC
February 2020

Adipocyte Specific HO-1 Gene Therapy is Effective in Antioxidant Treatment of Insulin Resistance and Vascular Function in an Obese Mice Model.

Antioxidants (Basel) 2020 Jan 1;9(1). Epub 2020 Jan 1.

Departments of Medicine and Pharmacology, New York Medical College, Valhalla, NY 10595, USA.

Obesity is a risk factor for vascular dysfunction and insulin resistance. The study aim was to demonstrate that adipocyte-specific HO-1 (heme oxygenase-1) gene therapy is a therapeutic approach for preventing the development of obesity-induced metabolic disease in an obese-mice model. Specific expression of HO-1 in adipose tissue was achieved by using a lentiviral vector expressing HO-1 under the control of the adiponectin vector (Lnv-adipo-HO-1). Mice fed a high-fat diet (HFD) developed adipocyte hypertrophy, fibrosis, decreased mitochondrial respiration, increased levels of inflammatory adipokines, insulin resistance, vascular dysfunction, and impaired heart mitochondrial signaling. These detrimental effects were prevented by the selective expression of HO-1 in adipocytes. Lnv-adipo-HO-1-transfected mice on a HFD display increased cellular respiration, increased oxygen consumption, increased mitochondrial function, and decreased adipocyte size. Moreover, RNA arrays confirmed that targeting adipocytes with HO-1 overrides the genetic susceptibility of adiposopathy and correlated with restoration of the expression of anti-inflammatory, thermogenic, and mitochondrial genes. Our data demonstrate that HO-1 gene therapy improved adipose tissue function and had positive impact on distal organs, suggesting that specific targeting of HO-1 gene therapy is an attractive therapeutic approach for improving insulin sensitivity, metabolic activity, and vascular function in obesity.
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http://dx.doi.org/10.3390/antiox9010040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7022335PMC
January 2020

Mitochondrial Metabolic Reprogramming by CD36 Signaling Drives Macrophage Inflammatory Responses.

Circ Res 2019 12 18;125(12):1087-1102. Epub 2019 Oct 18.

From the Blood Research Institute, Versiti, Blood Center of Wisconsin, Milwaukee (Y.C., W.H., Y.Z., M.L.S., Z.G., W. Cui, S.M., R.L.S.).

Rationale: A hallmark of chronic inflammatory disorders is persistence of proinflammatory macrophages in diseased tissues. In atherosclerosis, this is associated with dyslipidemia and oxidative stress, but mechanisms linking these phenomena to macrophage activation remain incompletely understood.

Objective: To investigate mechanisms linking dyslipidemia, oxidative stress, and macrophage activation through modulation of immunometabolism and to explore therapeutic potential targeting specific metabolic pathways.

Methods And Results: Using a combination of biochemical, immunologic, and ex vivo cell metabolic studies, we report that CD36 mediates a mitochondrial metabolic switch from oxidative phosphorylation to superoxide production in response to its ligand, oxidized LDL (low-density lipoprotein). Mitochondrial-specific inhibition of superoxide inhibited oxidized LDL-induced NF-κB (nuclear factor-κB) activation and inflammatory cytokine generation. RNA sequencing, flow cytometry, 3H-labeled palmitic acid uptake, lipidomic analysis, confocal and electron microscopy imaging, and functional energetics revealed that oxidized LDL upregulated effectors of long-chain fatty acid uptake and mitochondrial import, while downregulating fatty acid oxidation and inhibiting ATP5A (ATP synthase F1 subunit alpha)-an electron transport chain component. The combined effect is long-chain fatty acid accumulation, alteration of mitochondrial structure and function, repurposing of the electron transport chain to superoxide production, and NF-κB activation. null mice challenged with high-fat diet showed similar metabolic changes in circulating Ly6C monocytes and peritoneal macrophages, along with increased CD36 expression. Moreover, mitochondrial reactive oxygen species were positively correlated with CD36 expression in aortic lesional macrophages.

Conclusions: These findings reveal that oxidized LDL/CD36 signaling in macrophages links dysregulated fatty acid metabolism to oxidative stress from the mitochondria, which drives chronic inflammation. Thus, targeting to CD36 and its downstream effectors may serve as potential new strategies against chronic inflammatory diseases such as atherosclerosis.
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http://dx.doi.org/10.1161/CIRCRESAHA.119.315833DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6921463PMC
December 2019

Cardioprotective Heme Oxygenase-1-PGC1α Signaling in Epicardial Fat Attenuates Cardiovascular Risk in Humans as in Obese Mice.

Obesity (Silver Spring) 2019 10 23;27(10):1634-1643. Epub 2019 Aug 23.

Department of Pharmacology, New York Medical College, Valhalla, New York, USA.

Objective: This study investigated whether levels of signaling pathways and inflammatory adipokines in epicardial fat regulate cardiovascular risks in humans and mice.

Methods: Epicardial fat was obtained from the hearts of patients with heart failure requiring coronary artery bypass surgery, and signaling pathways were compared with visceral fat. The genetic profile of epicardial and visceral fat from humans was also compared with genetic profiles of epicardial and visceral fat in obese mice. Left ventricular (LV) fractional shortening was measured in obese mice before and after treatment with inducers of mitochondrial signaling heme oxygenase 1 (HO-1)-peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α). An RNA array/heat map on 88 genes that regulate adipose tissue function was used to identify a target gene network.

Results: Human epicardial fat gene profiling showed decreased levels of mitochondrial signaling of HO-1-PGC1α and increased levels of the inflammatory adipokine CCN family member 3. Similar observations were seen in epicardial and visceral fat of obese mice. Improvement in LV function was linked to the increase in mitochondrial signaling in epicardial fat of obese mice.

Conclusions: There is a link between cardiac ectopic fat deposition and cardiac function in humans that is similar to that which is described in obese mice. An increase of mitochondrial signaling pathway gene expression in epicardial fat attenuates cardiometabolic dysfunction and LV fractional shortening in obese mice.
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http://dx.doi.org/10.1002/oby.22608DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6756945PMC
October 2019

Early Rapid Decline in Kidney Function in Medically Managed Patients With Atherosclerotic Renal Artery Stenosis.

J Am Heart Assoc 2019 06 1;8(11):e012366. Epub 2019 Jun 1.

Joan C. Edwards School of Medicine Marshall University Huntington WV.

Background Early rapid declines of kidney function may occur in patients with atherosclerotic renal artery stenosis with institution of medical therapy. The causes and consequences are not well understood. Methods and Results Patients enrolled in the medical therapy-only arm of the CORAL (Cardiovascular Outcomes With Renal Artery Lesions) study were assessed for a rapid decline (RD) in estimated glomerular filtration rate (eGFR), defined as a ≥30% decrease from baseline to either 3 months, 6 months, or both. In the medical therapy-only cohort, eGFR was available in 359 subjects at all time points, the subjects were followed for a median of 4.72 years, and 66 of 359 (18%) subjects experienced an early RD. Baseline log cystatin C (odds ratio, 1.78 [1.11-2.85]; P=0.02), age (odds ratio, 1.04 [1.00-1.07]; P<0.05), and Chronic Kidney Disease Epidemiology Collaboration creatinine eGFR (odds ratio, 1.86 [1.15-3.0]; P=0.01) were associated with an early RD. Despite continued medical therapy only, the RD group had an improvement in eGFR at 1 year (6.9%; P=0.04). The RD and nondecline groups were not significantly different for clinical events and all-cause mortality (P=0.78 and P=0.76, respectively). Similarly, renal replacement therapy occurred in 1 of 66 (1.5%) of the RD patients and in 6 of 294 (2%) of the nondecline patients. The regression to the mean of improvement in eGFR at 1 year in the RD group was estimated at 5.8±7.1%. Conclusions Early rapid declines in kidney function may occur in patients with renal artery stenosis when medical therapy is initiated, and their clinical outcomes are comparable to those without such a decline, when medical therapy only is continued.
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http://dx.doi.org/10.1161/JAHA.119.012366DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6585374PMC
June 2019

Metabolic Syndrome and Salt-Sensitive Hypertension in Polygenic Obese TALLYHO/JngJ Mice: Role of Na/K-ATPase Signaling.

Int J Mol Sci 2019 Jul 16;20(14). Epub 2019 Jul 16.

Departments of Clinical & Translational Sciences, Biomedical Sciences, and Medicine, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25755, USA.

We have demonstrated that Na/K-ATPase acts as a receptor for reactive oxygen species (ROS), regulating renal Na handling and blood pressure. TALLYHO/JngJ (TH) mice are believed to mimic the state of obesity in humans with a polygenic background of type 2 diabetes. This present work is to investigate the role of Na/K-ATPase signaling in TH mice, focusing on susceptibility to hypertension due to chronic excess salt ingestion. Age-matched male TH and the control C57BL/6J (B6) mice were fed either normal diet or high salt diet (HS: 2, 4, and 8% NaCl) to construct the renal function curve. Na/K-ATPase signaling including c-Src and ERK1/2 phosphorylation, as well as protein carbonylation (a commonly used marker for enhanced ROS production), were assessed in the kidney cortex tissues by Western blot. Urinary and plasma Na levels were measured by flame photometry. When compared to B6 mice, TH mice developed salt-sensitive hypertension and responded to a high salt diet with a significant rise in systolic blood pressure indicative of a blunted pressure-natriuresis relationship. These findings were evidenced by a decrease in total and fractional Na excretion and a right-shifted renal function curve with a reduced slope. This salt-sensitive hypertension correlated with changes in the Na/K-ATPase signaling. Specifically, Na/K-ATPase signaling was not able to be stimulated by HS due to the activated baseline protein carbonylation, phosphorylation of c-Src and ERK1/2. These findings support the emerging view that Na/K-ATPase signaling contributes to metabolic disease and suggest that malfunction of the Na/K-ATPase signaling may promote the development of salt-sensitive hypertension in obesity. The increased basal level of renal Na/K-ATPase-dependent redox signaling may be responsible for the development of salt-sensitive hypertension in polygenic obese TH mice.
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http://dx.doi.org/10.3390/ijms20143495DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6678942PMC
July 2019

Beneficial Role of HO-1-SIRT1 Axis in Attenuating Angiotensin II-Induced Adipocyte Dysfunction.

Int J Mol Sci 2019 Jun 29;20(13). Epub 2019 Jun 29.

Department of Surgery, Internal Medicine, and Biomedical Sciences, Marshall University Joan C. Edwards School of Medicine, Huntington, WV 25701, USA.

Background: Angiotensin II (Ang II), released by the renin-angiotensin-aldosterone system (RAAS), contributes to the modulatory role of the RAAS in adipose tissue dysfunction. Investigators have shown that inhibition of AngII improved adipose tissue function and insulin resistance in mice with metabolic syndrome. Heme Oxygenase-1 (HO-1), a potent antioxidant, has been demonstrated to improve oxidative stress and adipocyte phenotype. Molecular effects of high oxidative stress include suppression of sirtuin-1 (SIRT1), which is amenable to redox manipulations. The mechanisms involved, however, in these metabolic effects of the RAAS remain incompletely understood.

Hypothesis: We hypothesize that AngII-induced oxidative stress has the potential to suppress adipocyte SIRT1 via down regulation of HO-1. This effect of AngII will, in turn, upregulate mineralocorticoid receptor (MR). The induction of HO-1 will rescue SIRT1, hence improving oxidative stress and adipocyte phenotype.

Methods And Results: We examined the effect of AngII on lipid accumulation, oxidative stress, and inflammatory cytokines in mouse pre-adipocytes in the presence and absence of cobalt protoporphyrin (CoPP), HO-1 inducer, tin mesoporphyrin (SnMP), and HO-1 inhibitor. Our results show that treatment of mouse pre-adipocytes with AngII increased lipid accumulation, superoxide levels, inflammatory cytokine levels, interleukin-6 (IL-6) and tumor necrosis factor α (TNFα), and adiponectin levels. This effect was attenuated by HO-1 induction, which was further reversed by SnMP, suggesting HO-1 mediated improvement in adipocyte phenotype. AngII-treated pre-adipocytes also showed upregulated levels of MR and suppressed SIRT1 that was rescued by HO-1. Subsequent treatment with CoPP and SIRT1 siRNA in mouse pre-adipocytes increased lipid accumulation and fatty acid synthase (FAS) levels, suggesting that beneficial effects of HO-1 are mediated via SIRT1.

Conclusion: Our study demonstrates for the first time that HO-1 has the ability to restore cellular redox, rescue SIRT1, and prevent AngII-induced impaired effects on adipocytes and the systemic metabolic profile.
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http://dx.doi.org/10.3390/ijms20133205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6650875PMC
June 2019

Information within residency monthly evaluation forms at two institutions.

Med Educ Online 2019 Dec;24(1):1635844

b Joan C. Edwards College of Medicine , Marshall University , Huntington , USA.

Periodic review of resident performance is an important aspect of residency training. Amongst allopathic residency programs, it is expected that the performance of resident physicians which can be grouped based on the ACGME core competencies, be assessed so as to allow for effective feedback and continuous improvement. Review of monthly evaluation forms for residents in the core ACGME programs at Marshall University and the University of Toledo demonstrated a wide spread in the number of Likert questions that faculty were asked to complete. This number ranged from a low of 7 in Surgery to a high of 65 in Psychiatry (both Marshall Programs). Correlation and network analysis were performed on these data. High degrees of correlations were noted between answers to questions (controlled for each resident) on these forms at both institutions. In other words, although evaluation scores varied tremendously amongst the different residents in all the programs studied, scores addressing different competencies tended to be very similar for the same resident, especially in some of the programs which were studied. Network analysis suggested that there were clusters of questions that produced essentially the same answer for a given resident, and these clusters were bigger in some of the different residency program assessment forms. This seemed to be more the rule in the residency programs with large numbers of Likert questions. The authors suggest that reducing the number of monthly questions used to address the core competencies in some programs may be possible without substantial loss of information.
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http://dx.doi.org/10.1080/10872981.2019.1635844DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6610528PMC
December 2019

The Adipocyte Na/K-ATPase Oxidant Amplification Loop is the Central Regulator of Western Diet-Induced Obesity and Associated Comorbidities.

Sci Rep 2019 05 28;9(1):7927. Epub 2019 May 28.

Departments of Medicine, Surgery, Biomedical Sciences, and Healthcare Informatics Program, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, USA.

Obesity has become a worldwide epidemic. We have previously reported that systemic administration of pNaKtide which targets the Na/K-ATPase oxidant amplification loop (NKAL) was able to decrease systemic oxidative stress and adiposity in mice fed a high fat and fructose supplemented western diet (WD). As adipocytes are believed to play a central role in the development of obesity and its related comorbidities, we examined whether lentiviral-mediated adipocyte-specific expression of NaKtide, a peptide derived from the N domain of the alpha1 Na/K-ATPase subunit, could ameliorate the effects of the WD. C57BL6 mice were fed a WD, which activated Na/K-ATPase signaling in the adipocytes and induced an obese phenotype and caused an increase in plasma levels of leptin, IL-6 and TNFα. WD also decreased locomotor activity, expression of the D2 receptor and tyrosine hydroxylase in brain tissue, while markers of neurodegeneration and neuronal apoptosis were increased following the WD. Selective adipocyte expression of NaKtide in these mice fed a WD attenuated all of these changes including the brain biochemical alterations and behavioral adaptations. These data suggest that adipocyte derived cytokines play an essential role in the development of obesity induced by a WD and that targeting the adipocyte NKAL loop may serve as an effective therapeutic strategy.
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http://dx.doi.org/10.1038/s41598-019-44350-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6538745PMC
May 2019

Prediction of cardiovascular outcomes with machine learning techniques: application to the Cardiovascular Outcomes in Renal Atherosclerotic Lesions (CORAL) study.

Int J Nephrol Renovasc Dis 2019 21;12:49-58. Epub 2019 Mar 21.

Marshall University, Huntington, WV, USA,

Background: Data derived from the Cardiovascular Outcomes in Renal Atherosclerotic Lesions (CORAL) study were analyzed in an effort to employ machine learning methods to predict the composite endpoint described in the original study.

Methods: We identified 573 CORAL subjects with complete baseline data and the presence or absence of a composite endpoint for the study. These data were subjected to several models including a generalized linear (logistic-linear) model, support vector machine, decision tree, feed-forward neural network, and random forest, in an effort to attempt to predict the composite endpoint. The subjects were arbitrarily divided into training and testing subsets according to an 80%:20% distribution with various seeds. Prediction models were optimized within the CARET package of R.

Results: The best performance of the different machine learning techniques was that of the random forest method which yielded a receiver operator curve (ROC) area of 68.1%±4.2% (mean ± SD) on the testing subset with ten different seed values used to separate training and testing subsets. The four most important variables in the random forest method were SBP, serum creatinine, glycosylated hemoglobin, and DBP. Each of these variables was also important in at least some of the other methods. The treatment assignment group was not consistently an important determinant in any of the models.

Conclusion: Prediction of a composite cardiovascular outcome was difficult in the CORAL population, even when employing machine learning methods. Assignment to either the stenting or best medical therapy group did not serve as an important predictor of composite outcome.

Clinical Trial Registration: ClinicalTrials.gov, NCT00081731.
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http://dx.doi.org/10.2147/IJNRD.S194727DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6433104PMC
March 2019