Scholars@Duke
Conrad Phillip Hodgkinson

Conrad Phillip Hodgkinson

Associate Professor in Medicine
Medicine, Cardiology
conrad.hodgkinson@duke.edu
213 Research Drive, CARL 0122, Box 102145, Durham, NC 27710

Selected Publications

The impact of aging on cardiac repair and regeneration.

Journal Article J Biol Chem · September 2024 In contrast to neonates and lower organisms, the adult mammalian heart lacks any capacity to regenerate following injury. The vast majority of our understanding of cardiac regeneration is based on research in young animals. Research in aged individuals is ... Full text Link to item Cite

Modifying miRs for effective reprogramming of fibroblasts to cardiomyocytes.

Journal Article Mol Ther Nucleic Acids · June 11, 2024 Reprogramming scar fibroblasts into cardiomyocytes has been proposed to reverse the damage associated with myocardial infarction. However, the limited improvement in cardiac function calls for enhanced strategies. We reported enhanced efficacy of our miR r ... Full text Link to item Cite

C166 EVs potentiate miR cardiac reprogramming via miR-148a-3p.

Journal Article J Mol Cell Cardiol · May 2024 We have demonstrated that directly reprogramming cardiac fibroblasts into new cardiomyocytes via miR combo improves cardiac function in the infarcted heart. However, major challenges exist with delivery and efficacy. During a screening based approach to im ... Full text Link to item Cite

Skeletal muscle differentiation induces wide-ranging nucleosome repositioning in muscle gene promoters.

Journal Article Sci Rep · April 24, 2024 In a previous report, we demonstrated that Cbx1, PurB and Sp3 inhibited cardiac muscle differentiation by increasing nucleosome density around cardiac muscle gene promoters. Since cardiac and skeletal muscle express many of the same proteins, we asked if C ... Full text Link to item Cite

Precision Hypertension.

Journal Article Hypertension · April 2024 Hypertension affects >1 billion people worldwide. Complications of hypertension include stroke, renal failure, cardiac hypertrophy, myocardial infarction, and cardiac failure. Despite the development of various antihypertensive drugs, the number of people ... Full text Link to item Cite

RNA Therapeutics for the Cardiovascular System.

Journal Article Circulation · February 27, 2024 RNA therapeutics hold significant promise in the treatment of cardiovascular diseases. RNAs are biologically diverse and functionally specific and can be used for gain- or loss-of-function purposes. The effectiveness of mRNA-based vaccines in the recent CO ... Full text Link to item Cite

Neonatal and adult cardiac fibroblasts exhibit inherent differences in cardiac regenerative capacity.

Journal Article J Biol Chem · May 2023 Directly reprogramming fibroblasts into cardiomyocytes improves cardiac function in the infarcted heart. However, the low efficacy of this approach hinders clinical applications. Unlike the adult mammalian heart, the neonatal heart has an intrinsic regener ... Full text Link to item Cite

Rig1 receptor plays a critical role in cardiac reprogramming via YY1 signaling.

Journal Article American journal of physiology. Cell physiology · April 2023 We discovered that innate immunity plays an important role in the reprogramming of fibroblasts into cardiomyocytes. In this report, we define the role of a novel retinoic acid-inducible gene 1 Yin Yang 1 (Rig1:YY1) pathway. We found that fibroblast to card ... Full text Cite

Novel method of differentiating human induced pluripotent stem cells to mature cardiomyocytes via Sfrp2.

Journal Article Sci Rep · March 9, 2023 Current methods to generate cardiomyocytes from induced pluripotent stem cells (iPSc) utilize broad-spectrum pharmacological inhibitors. These methods give rise to cardiomyocytes which are typically immature. Since we have recently demonstrated that cardio ... Full text Link to item Cite

Conservation of miR combo based direct cardiac reprogramming

Journal Article Biochemistry and Biophysics Reports · September 1, 2022 There is considerable interest in regenerating the injured heart by reprogramming resident fibroblasts into new functional cardiomyocytes. Cardiac reprogramming has been achieved via transcription factors or miRNAs. Transcription factor combinations appear ... Full text Cite

A novel Cbx1, PurB, and Sp3 complex mediates long-term silencing of tissue- and lineage-specific genes.

Journal Article J Biol Chem · June 2022 miRNA-based cellular fate reprogramming offers an opportunity to investigate the mechanisms of long-term gene silencing. To further understand how genes are silenced in a tissue-specific manner, we leveraged our miRNA-based method of reprogramming fibrobla ... Full text Link to item Cite

A role for Sfrp2 in cardiomyogenesis in vivo.

Journal Article Proc Natl Acad Sci U S A · August 17, 2021 Cardiomyogenesis, the process by which the body generates cardiomyocytes, is poorly understood. We have recently shown that Sfrp2 promotes cardiomyogenesis in vitro. The objective of this study was to determine if Sfrp2 would similarly promote cardiomyogen ... Full text Link to item Cite

Enhancing cardiac reprogramming via synthetic RNA oligonucleotides.

Journal Article Mol Ther Nucleic Acids · March 5, 2021 Reprogramming scar fibroblasts into new heart muscle cells has the potential to restore function to the injured heart. However, the effectiveness of reprogramming is notably low. We have recently demonstrated that the effectiveness of reprogramming fibrobl ... Full text Link to item Cite

The role of Sfrp and DKK proteins in cardiomyocyte development.

Journal Article Physiol Rep · February 2021 In this review, we summarize the role of Wnt proteins in cardiomyogenesis. More specifically, we focus on how the development of cardiomyocytes from precursor cells involves a complex interplay between Wnt canonical β-catenin signaling pathways and Wnt non ... Full text Link to item Cite

Production of Cardiomyocytes by microRNA-Mediated Reprogramming in Optimized Reprogramming Media.

Journal Article Methods Mol Biol · 2021 There are currently no effective treatments to regenerate the heart after cardiac injury. Following cardiac injury, heart muscle cells, also known as cardiomyocytes, die in large numbers. The adult mammalian heart does not have the ability to replace these ... Full text Link to item Cite

Sequential paracrine mechanisms are necessary for the therapeutic benefits of stem cell therapy.

Journal Article Am J Physiol Cell Physiol · December 1, 2020 Stem cell injections are an attractive therapeutic tool. It has been demonstrated that injected stem cells promote tissue repair and regeneration via paracrine mechanisms. However, the effects of injected stem cells continue for far longer than they are pr ... Full text Link to item Cite

Optimizing delivery for efficient cardiac reprogramming.

Journal Article Biochem Biophys Res Commun · November 26, 2020 Following heart injury, cardiomyocytes, are lost and are not regenerated. In their place, fibroblasts invade the dead tissue where they generate a scar, which reduces cardiac function. We and others have demonstrated that combinations of specific miRNAs (m ... Full text Link to item Cite

Sox6 as a new modulator of renin expression in the kidney.

Journal Article Am J Physiol Renal Physiol · February 1, 2020 Juxtaglomerular (JG) cells, major sources of renin, differentiate from metanephric mesenchymal cells that give rise to JG cells or a subset of smooth muscle cells of the renal afferent arteriole. During periods of dehydration and salt deprivation, renal me ... Full text Link to item Cite

Induced cardiomyocyte maturation: Cardiac transcription factors are necessary but not sufficient.

Journal Article PLoS One · 2019 The process by which fibroblasts are directly reprogrammed into cardiomyocytes involves two stages; initiation and maturation. Initiation represents the initial expression of factors that induce fibroblasts to transdifferentiate into cardiomyocytes. Follow ... Full text Link to item Cite

Insights from molecular signature of in vivo cardiac c-Kit(+) cells following cardiac injury and β-catenin inhibition.

Journal Article J Mol Cell Cardiol · October 2018 There is much interest over resident c-Kit(+) cells in tissue regeneration. Their role in cardiac regeneration has been controversial. In this study we aim to understand the in vivo behavior of cardiac c-Kit(+) cells at baseline and after myocardial infarc ... Full text Link to item Cite

Cardiomyocyte Maturation Requires TLR3 Activated Nuclear Factor Kappa B.

Journal Article Stem Cells · August 2018 The process by which committed precursors mature into cardiomyocytes is poorly understood. We found that TLR3 inhibition blocked cardiomyocyte maturation; precursor cells committed to the cardiomyocyte lineage failed to express maturation genes and sarcome ... Full text Link to item Cite

Understanding the mechanism of bias signaling of the insulin-like growth factor 1 receptor: Effects of LL37 and HASF.

Journal Article Cell Signal · June 2018 The development of biased agonist drugs is widely recognized to be important for the treatment of many diseases, including cardiovascular disease. While GPCR biased agonism has been heavily characterized there is a distinct lack of information with respect ... Full text Link to item Cite

The proximity-labeling technique BioID identifies sorting nexin 6 as a member of the insulin-like growth factor 1 (IGF1)-IGF1 receptor pathway.

Journal Article J Biol Chem · April 27, 2018 The insulin-like growth factor 1 receptor (IGF1R) is a receptor tyrosine kinase with critical roles in various biological processes. Recent results from clinical trials targeting IGF1R indicate that IGF1R signaling pathways are more complex than previously ... Full text Link to item Cite

Demethylation of H3K27 Is Essential for the Induction of Direct Cardiac Reprogramming by miR Combo.

Journal Article Circ Res · April 28, 2017 RATIONALE: Direct reprogramming of cardiac fibroblasts to cardiomyocytes has recently emerged as a novel and promising approach to regenerate the injured myocardium. We have previously demonstrated the feasibility of this approach in vitro and in vivo usin ... Full text Link to item Cite

HASF (C3orf58) is a novel ligand of the insulin-like growth factor 1 receptor.

Journal Article Biochem J · February 20, 2017 We have recently shown that hypoxia and Akt-induced stem cell factor (HASF) protects the heart from ischemia-induced damage and promotes cardiomyocyte proliferation. While we have identified certain signaling pathways responsible for these protective effec ... Full text Link to item Cite

Tissue-engineered 3-dimensional (3D) microenvironment enhances the direct reprogramming of fibroblasts into cardiomyocytes by microRNAs.

Journal Article Sci Rep · December 12, 2016 We have recently shown that a combination of microRNAs, miR combo, can directly reprogram cardiac fibroblasts into functional cardiomyocytes in vitro and in vivo. Reprogramming of cardiac fibroblasts by miR combo in vivo is associated with improved cardiac ... Full text Link to item Cite

Selenium Augments microRNA Directed Reprogramming of Fibroblasts to Cardiomyocytes via Nanog.

Journal Article Sci Rep · March 15, 2016 We have recently shown that a combination of microRNAs, miR combo, can directly reprogram cardiac fibroblasts into functional cardiomyocytes in vitro and in vivo. However, direct reprogramming strategies are inefficient and slow. Moving towards the eventua ... Full text Link to item Cite

Emerging Concepts in Paracrine Mechanisms in Regenerative Cardiovascular Medicine and Biology.

Journal Article Circ Res · January 8, 2016 In the past decade, substantial evidence supports the paradigm that stem cells exert their reparative and regenerative effects, in large part, through the release of biologically active molecules acting in a paracrine fashion on resident cells. The data su ... Full text Link to item Cite

MicroRNAs and Cardiac Regeneration.

Journal Article Circ Res · May 8, 2015 The human heart has a limited capacity to regenerate lost or damaged cardiomyocytes after cardiac insult. Instead, myocardial injury is characterized by extensive cardiac remodeling by fibroblasts, resulting in the eventual deterioration of cardiac structu ... Full text Link to item Cite

MicroRNA induced cardiac reprogramming in vivo: evidence for mature cardiac myocytes and improved cardiac function.

Journal Article Circ Res · January 30, 2015 RATIONALE: A major goal for the treatment of heart tissue damaged by cardiac injury is to develop strategies for restoring healthy heart muscle through the regeneration and repair of damaged myocardium. We recently demonstrated that administration of a spe ... Full text Link to item Cite

Role of Paracrine Mechanisms

Chapter · January 1, 2015 Many studies have demonstrated that the exogenous delivery of stem cells into injured myocardium results in functional improvements. It was originally thought that the regenerative properties of these stem cells arose from engraftment into the myocardium a ... Full text Cite

Abi3bp regulates cardiac progenitor cell proliferation and differentiation.

Journal Article Circ Res · December 5, 2014 RATIONALE: Cardiac progenitor cells (CPCs) are thought to differentiate into the major cell types of the heart: cardiomyocytes, smooth muscle cells, and endothelial cells. We have recently identified ABI family, member 3 (NESH) binding protein (Abi3bp) as ... Full text Link to item Cite

HASF is a stem cell paracrine factor that activates PKC epsilon mediated cytoprotection.

Journal Article J Mol Cell Cardiol · January 2014 Despite advances in the treatment of acute tissue ischemia significant challenges remain in effective cytoprotection from ischemic cell death. It has been documented that injected stem cells, such as mesenchymal stem cells (MSCs), can confer protection to ... Full text Link to item Cite

Abi3bp is a multifunctional autocrine/paracrine factor that regulates mesenchymal stem cell biology.

Journal Article Stem Cells · August 2013 Mesenchymal stem cells (MSCs) transplanted into injured myocardium promote repair through paracrine mechanisms. We have previously shown that MSCs over-expressing AKT1 (Akt-MSCs) exhibit enhanced properties for cardiac repair. In this study, we investigate ... Full text Link to item Cite

Toll-like receptors and human disease: Lessons from single nucleotide polymorphisms

Journal Article Current Genomics · December 3, 2012 Toll-like receptors (TLRs), a large group of proteins which recognize various pathogen-associated molecular patterns, are critical for the normal function of the innate immune system. Following their discovery many single nucleotide polymorphisms within TL ... Full text Cite

Toll-like receptors, their ligands, and atherosclerosis.

Journal Article ScientificWorldJournal · February 14, 2011 Atherosclerosis is a disease characterized by inflammation in the arterial wall. Atherogenesis is dependent on the innate immune response involving activation of Toll-like receptors (TLRs) and the expression of inflammatory proteins. TLRs, which recognize ... Full text Link to item Cite

Genetic engineering of mesenchymal stem cells and its application in human disease therapy.

Journal Article Hum Gene Ther · November 2010 The use of stem cells for tissue regeneration and repair is advancing both at the bench and bedside. Stem cells isolated from bone marrow are currently being tested for their therapeutic potential in a variety of clinical conditions including cardiovascula ... Full text Open Access Link to item Cite

A role of matrix metalloproteinase-8 in atherosclerosis.

Journal Article Circ Res · October 23, 2009 RATIONALE: Atherosclerotic lesions express matrix metalloproteinase (MMP)8, which possesses proteolytic activity on matrix proteins particularly fibrillar collagens and on nonmatrix proteins such as angiotensin (Ang) I. OBJECTIVE: We studied whether MMP8 p ... Full text Link to item Cite

Advanced glycation end-product of low density lipoprotein activates the toll-like 4 receptor pathway implications for diabetic atherosclerosis.

Journal Article Arterioscler Thromb Vasc Biol · December 2008 OBJECTIVE: Diabetes is a major risk factor for coronary heart disease. Accumulation of advanced glycation end-products (AGEs) attributable to hyperglycemia in diabetics promotes the development of atherosclerosis. However, the underlying mechanisms remain ... Full text Link to item Cite

Statins inhibit toll-like receptor 4-mediated lipopolysaccharide signaling and cytokine expression.

Journal Article Pharmacogenet Genomics · September 2008 OBJECTIVE: Toll-like receptor 4 (TLR4) is the main receptor for Lipopolysaccharide (LPS). Two relatively common variants of the TLR4 gene are present, resulting in changes from aspartic acid (D) to glycine (G) at residue 299 and from threonine (T) to isole ... Full text Link to item Cite

Functional Toll-like receptor 4 mutations modulate the response to fibrinogen.

Journal Article Thromb Haemost · August 2008 Fibrinogen has been implicated in atherosclerosis; in part by activating the lipopolysaccharide (LPS) receptor Toll-like receptor 4 (TLR4). The fibrinogen-TLR4 signalling pathway remains uncharacterised. In human macrophages fibrinogen stimulated interleuk ... Link to item Cite

Insulin-triggered repositioning of munc18c on syntaxin-4 in GLUT4 signalling.

Journal Article Biochem J · March 1, 2008 One of the most important actions of insulin is the stimulation of the uptake of glucose into fat and muscle cells. Crucial to this response is the translocation of GLUT4 (glucose transporter-4) to the plasma membrane. The insulin-stimulated GLUT4 vesicle ... Full text Link to item Cite

80K-H acts as a signaling bridge in intact living cells between PKCzeta and the GLUT4 translocation regulator Munc18c.

Journal Article J Recept Signal Transduct Res · 2008 Insulin triggers the translocation of glucose transporter GLUT4 to the plasma membrane. To understand the nature of the missing links between upstream insulin activated kinases and proteins of the GLUT4 translocation apparatus, the role of 80K-H was examin ... Full text Link to item Cite

Association of matrix metalloproteinase-8 gene variation with breast cancer prognosis.

Journal Article Cancer Res · November 1, 2007 Animal and cell studies indicate an inhibitory effect of matrix metalloproteinase-8 (MMP8) on tumorigenesis and metastasis. We investigated whether MMP8 gene variation was associated with breast cancer metastasis and prognosis in humans. We first studied n ... Full text Link to item Cite

Functional polymorphism in ABCA1 influences age of symptom onset in coronary artery disease patients.

Journal Article Hum Mol Genet · June 15, 2007 ATP-binding-cassette-transporter-A1 (ABCA1) plays a pivotal role in intracellular cholesterol removal, exerting a protective effect against atherosclerosis. ABCA1 gene severe mutations underlie Tangier disease, a rare Mendelian disorder that can lead to pr ... Full text Link to item Cite

A new strategy for studying protein kinase B and its three isoforms. Role of protein kinase B in phosphorylating glycogen synthase kinase-3, tuberin, WNK1, and ATP citrate lyase.

Journal Article Biochemistry · January 10, 2006 Protein kinase B appears to play a key role in insulin signaling and in the control of apoptosis, although the precise targets of PKB are incompletely understood. PKB exists as three isoforms (alpha, beta, and gamma) that may have unique as well as common ... Full text Link to item Cite

Protein kinase-zeta interacts with munc18c: role in GLUT4 trafficking.

Journal Article Diabetologia · August 2005 AIMS/HYPOTHESIS: Insulin-stimulated glucose transport requires a signalling cascade through kinases protein kinase (PK) Czeta/lambda and PKB that leads to movement of GLUT4 vesicles to the plasma membrane. The aim of this study was to identify missing link ... Full text Link to item Cite

Identification of 80K-H as a protein involved in GLUT4 vesicle trafficking.

Journal Article Biochem J · June 15, 2005 PKCzeta (protein kinase Czeta) is a serine/threonine protein kinase controlled by insulin, various growth factors and phosphoinositide 3-kinase. It has been implicated in controlling glucose transport in response to insulin by the translocation of GLUT4-(g ... Full text Link to item Cite

Knock-down of LAR protein tyrosine phosphatase induces insulin resistance.

Journal Article FEBS Lett · June 6, 2005 To test the role of the leukocyte common antigen-related protein tyrosine phosphatase (LAR) as a regulator of insulin receptor (IR) signalling, an siRNA probe against LAR was developed. Knock-down of LAR induced post-receptor insulin resistance with the in ... Full text Link to item Cite

Genotypic effect of the -565C>T polymorphism in the ABCA1 gene promoter on ABCA1 expression and severity of atherosclerosis.

Journal Article Arterioscler Thromb Vasc Biol · February 2005 OBJECTIVE: Loss-of-function mutations of the ATP-binding cassette transporter A1 (ABCA1) gene cause Tangier disease, a rare genetic disorder with accumulation of lipid-laden macrophages and increased risk of atherosclerosis. Common variants of this gene ma ... Full text Link to item Cite

Microarray analysis of peroxisome proliferator-activated receptor-gamma induced changes in gene expression in macrophages.

Journal Article Biochem Biophys Res Commun · August 29, 2003 We used a combination of expression microarray and Northern blot analyses to identify target genes for peroxisome proliferator-activated receptor (PPAR) gamma in RAW264.7 macrophages. PPARgamma natural ligand 15-deoxy-Delta(12,14) prostaglandin and synthet ... Full text Link to item Cite

Characterization of PDK2 activity against protein kinase B gamma.

Journal Article Biochemistry · August 13, 2002 Protein kinase B (PKB), also known as Akt, is a serine/threonine protein kinase controlled by insulin, various growth factors, and phosphatidylinositol 3-kinase. Full activation of the PKB enzyme requires phosphorylation of a threonine in the activation lo ... Full text Link to item Cite

Regulation of both PDK1 and the phosphorylation of PKC-zeta and -delta by a C-terminal PRK2 fragment.

Journal Article Biochemistry · January 15, 2002 The mechanism by which PDK1 regulates AGC kinases remains unclear. To further understand this process, we performed a yeast two-hybrid screen using PDK1 as bait. PKC-zeta, PKC-delta, and PRK2 were identified as interactors of PDK1. A combination of yeast t ... Full text Link to item Cite

Fibronectin-mediated hepatocyte shape change reprograms cytochrome P450 2C11 gene expression via an integrin-signaled induction of ribonuclease activity.

Journal Article Mol Pharmacol · November 2000 A major limitation to the use of rat hepatocytes in the study of drug metabolism and toxicity is the rapid loss of CYPs. We demonstrate that the culture of rat hepatocytes results in a rapid loss of liver-specific CYP2C11 mRNA and transcripts encoding the ... Full text Link to item Cite

Temperature-sensitive mRNA degradation is an early event in hepatocyte de-differentiation.

Journal Article Biochem J · December 15, 1997 The isolation and culture of metabolically active hepatocytes by proteolytic digestion of the extracellular matrix of the liver results in the transcriptional silencing of liver-specific genes encoding cytochromes P-450 (CYP) and albumin together with an i ... Full text Link to item Cite