Abstract 272: miRNA-7 Leads to Enhanced Fibrosis in the Heart

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Manveen Gupta ◽  
Xi Wang ◽  
Elizabeth Martelli ◽  
Prasad Sathyamangla
Keyword(s):  
Cardiac Dysfunction ◽  
Critical Role ◽  
Human Heart Failure ◽  
Hypertrophic Response ◽  
Erbb2 Expression ◽  
Kaplan Meier ◽  
Response To Stress ◽  
Epidermal Growth ◽  
Egfr Family ◽  
And Function

MicroRNA-7 (miR-7) is known to target epidermal growth factor receptors (EGFRs) in oncogenic cells however, less is known about its role and function in the heart. Our studies have identified reciprocal expression pattern for ERBB2 (a member of EGFR family) in the context of miR-7 expression in human heart failure and in mice post-TAC (Transverse Aortic Constriction). To directly determine the role of miR-7 in the heart, we generated transgenic (Tg) mice with cardiomyocyte-specific overexpression of miR-7 (miR-7 Tg). miR-7 Tg mice are characterized by marked loss in ERBB2 expression compared to their wildtype littermate controls. Also, miR-7 Tg mice have age-dependent deterioration in cardiac dysfunction and is associated with dilation as measured by echocardiography (3 months - 60% FS, 6 month -52% FS and 12 months - 24%FS) and yet, they survive over 18 months as assessed by Kaplan-Meier curves. To investigate whether pathological stress would accelerate the deterioration in cardiac function, miR-7 Tg mice were subjected to TAC for two weeks. In contrast to the wild type littermates that showed significant hypertrophic response, miR-7 Tg mice have accelerated cardiac dysfunction and dilation following two weeks of TAC. Histological analysis shows increased collagen deposition in miR-7 Tg mice which is further accelerated following after TAC compared to their sham controls. These observations suggest that ERBB2 expression in the cardiomyocytes may play a critical role in delaying the pro-fibrotic response post-TAC by supporting an adaptive hypertrophic response in response to stress. Our study will discuss the mechanisms of increased fibrosis observed in miR-7 Tg mice subjected to TAC.

Abstract 120: Epidermal Growth Factor Receptor (EGFR) Family Dimeric Partners Switch During Pathological Stress in microRNA-7 Transgenic Mice

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Manveen Gupta ◽  
Xi Wang ◽  
Elizabeth Martelli ◽  
Sathyamangla V Naga Prasad
Keyword(s):  
Cardiac Dysfunction ◽  
Biochemical Analysis ◽  
Growth Factor Receptor ◽  
Aortic Constriction ◽  
Human Heart Failure ◽  
Hypertrophic Response ◽  
Downstream Signaling ◽  
Age Dependent ◽  
Epidermal Growth ◽  
Egfr Family

miRNA-7 is known to target epidermal growth factors receptor 1(EGFR1) in cancer cells. EGFR family members (EGFR 1, 2, 3 and 4) are known to form homo- and/or hetero-dimers to mediate downstream signals . Our previous study in human heart failure (Naga Prasad etal., JBC, 2009) showed that EGFR2 (ERBB2) was targeted by miRNA-7. Based on this study, we developed transgenic (Tg) mice with cardiomyocyte-specific overexpression of miRNA-7. miRNA-7 Tg mice have age dependent deterioration in cardiac dysfunction and is associated with cardiac dilation as measured by echocardiography (3 months - 60% FS, 6 month -52% FS &12 months - 24%FS) and yet, they survive well for more than a year. To investigate whether pathological stress would accelerate the deterioration in cardiac function, miRNA-7 Tg mice were subjected to transverse aortic constriction (TAC) for two weeks. In contrast to the wild type littermates which undergo hypertrophic response following TAC, miRNA-7 Tg mice have accelerated cardiac dysfunction and dilation within two weeks. Biochemical analysis interestingly showed differential switching of dimeric EGFR partners in hearts of the miRNA-7 Tg mice compared to their sham controls. Our presentation will discuss the differential downstream signaling induced by changing of EGFR dimeric partners induced by pathological stress like TAC in the wildtype and miRNA-7 Tg mice.

scholarly journals The Catalytic Activity of the ErbB-2 Receptor Tyrosine Kinase Is Essential for Embryonic Development

2002 ◽  
Vol 22 (4) ◽  
pp. 1073-1078 ◽  
Author(s):  
Richard Chan ◽  
William R. Hardy ◽  
Michael A. Laing ◽  
Sarah E. Hardy ◽  
William J. Muller
Keyword(s):  
Catalytic Activity ◽  
Embryonic Development ◽  
Transcriptional Control ◽  
Biological Activities ◽  
Critical Role ◽  
Growth Factor Receptor ◽  
Knockout Mutants ◽  
Receptor Interactions ◽  
Epidermal Growth ◽  
Egfr Family

ABSTRACT Activation of the epidermal growth factor receptor (EGFR) family is thought to play a critical role in both embryogenesis and oncogenesis. The diverse biological activities of the EGFR family are achieved through various ligand-receptor and receptor-receptor interactions. One receptor that has been found to play a central role in this signaling network is ErbB-2/Neu, and it is considered the preferred heterodimerization partner for other members of the EGFR family. To assess the importance of the catalytic activity of ErbB-2 in embryonic development, we have generated mice expressing a kinase-dead erbB-2 cDNA under the transcriptional control of the endogenous promoter. Here, we show that mice homozygous for the kinase-dead erbB-2 allele die at midgestation and display the same spectrum of embryonic defects seen in erbB-2 knockout mutants. These observations suggest that the catalytic activity of ErbB-2 is essential for normal embryonic development.

scholarly journals Control Of Phosphoinositide Synthesis And Degradation By The Acyltransferase Lycat

2021 ◽  
Author(s):  
Yasmin Awadeh
Keyword(s):  
Intracellular Signaling ◽  
Critical Role ◽  
Membrane Traffic ◽  
New Information ◽  
Selective Incorporation ◽  
Lipid Kinases ◽  
Membrane Compartments ◽  
Epidermal Growth ◽  
And Function

Phosphoinositides (PIPs) are important regulators of various cellular phenomena including intracellular signaling, membrane traffic and cell migration. PIPs are formed as a result of the regulated phosphorylation of the inositol headgroup of phosphatidylinositol (PI) on specific positions by certain lipid kinases and phosphatases. It is well appreciated that the enrichment of specific PIPs, defined by inositol headgroup phosphorylation, within specific membrane compartments plays a critical role in organelle identity and membrane traffic. However, while much attention has been given to understanding of the role of inositol headgroup phosphorylation in PIP function, much less is known about the role of dynamic incorporation of specific acyl groups into these phospholipids. Importantly, PI and PIPs exhibit remarkable and unique selectivity for certain acyl groups. For example, about 45% of PIs (but not other phospholipids) are rich in 1-steroyl 2-arachidonyl. We recently identified that the possible control of the selective incorporation of steric acid at the sn-1 position is by the acyltransferase LYCAT, which controls the levels, acyl profile and function of phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2) (Bone et al. Mol Biol Cell 2017. 28:161-172). Here we examine how perturbation of LYCAT leads to a reduction in the levels of PI(4,5)P2 and phosphatidylinositol-3,4,5-trisphosphate (PI(3,4,5)P3). To measure the rate of PI(4,5)P2 synthesis, we treated cells with ionomycin to first ablate this PIP, followed by washout of the drug and monitoring of rate of reappearance via localization of a fluorescent PI(4,5)P2 probe. To measure the rate of PI(4,5)P2 degradation, we arrested PI(4,5)P2 synthesis by a pharmacological inhibitor, phenylarsine oxide (PAO) and monitored the loss of cellular PI(4,5)P2. Lastly, to examine the production of PI(3,4,5)P3, we treated cells with epidermal growth factor (EGF) and monitored the production of this PIP. Together, this work provides new information about how the dynamic and selective remodeling of specific phospholipids controls their levels, localization and function.

scholarly journals Cardiac expression of microRNA-7 is associated with adverse cardiac remodeling

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Manveen K. Gupta ◽  
Anita Sahu ◽  
Yu Sun ◽  
Maradumane L. Mohan ◽  
Avinash Kumar ◽  
...  
Keyword(s):  
Growth Factor Receptor ◽  
Significant Loss ◽  
Transverse Aortic Constriction ◽  
Cardiac Physiology ◽  
Aortic Constriction ◽  
Hypertrophic Response ◽  
Erbb2 Expression ◽  
Physiological Cardiac Hypertrophy ◽  
Epidermal Growth

AbstractAlthough microRNA-7 (miRNA-7) is known to regulate proliferation of cancer cells by targeting Epidermal growth factor receptor (EGFR/ERBB) family, less is known about its role in cardiac physiology. Transgenic (Tg) mouse with cardiomyocyte-specific overexpression of miRNA-7 was generated to determine its role in cardiac physiology and pathology. Echocardiography on the miRNA-7 Tg mice showed cardiac dilation instead of age-associated physiological cardiac hypertrophy observed in non-Tg control mice. Subjecting miRNA-7 Tg mice to transverse aortic constriction (TAC) resulted in cardiac dilation associated with increased fibrosis bypassing the adaptive cardiac hypertrophic response to TAC. miRNA-7 expression in cardiomyocytes resulted in significant loss of ERBB2 expression with no changes in ERBB1 (EGFR). Cardiac proteomics in the miRNA-7 Tg mice showed significant reduction in mitochondrial membrane structural proteins compared to NTg reflecting role of miRNA-7 beyond the regulation of EGFR/ERRB in mediating cardiac dilation. Consistently, electron microscopy showed that miRNA-7 Tg hearts had disorganized rounded mitochondria that was associated with mitochondrial dysfunction. These findings show that expression of miRNA-7 in the cardiomyocytes results in cardiac dilation instead of adaptive hypertrophic response during aging or to TAC providing insights on yet to be understood role of miRNA-7 in cardiac function.

scholarly journals Control Of Phosphoinositide Synthesis And Degradation By The Acyltransferase Lycat

2021 ◽  
Author(s):  
Yasmin Awadeh
Keyword(s):  
Intracellular Signaling ◽  
Critical Role ◽  
Membrane Traffic ◽  
New Information ◽  
Selective Incorporation ◽  
Lipid Kinases ◽  
Membrane Compartments ◽  
Epidermal Growth ◽  
And Function

Phosphoinositides (PIPs) are important regulators of various cellular phenomena including intracellular signaling, membrane traffic and cell migration. PIPs are formed as a result of the regulated phosphorylation of the inositol headgroup of phosphatidylinositol (PI) on specific positions by certain lipid kinases and phosphatases. It is well appreciated that the enrichment of specific PIPs, defined by inositol headgroup phosphorylation, within specific membrane compartments plays a critical role in organelle identity and membrane traffic. However, while much attention has been given to understanding of the role of inositol headgroup phosphorylation in PIP function, much less is known about the role of dynamic incorporation of specific acyl groups into these phospholipids. Importantly, PI and PIPs exhibit remarkable and unique selectivity for certain acyl groups. For example, about 45% of PIs (but not other phospholipids) are rich in 1-steroyl 2-arachidonyl. We recently identified that the possible control of the selective incorporation of steric acid at the sn-1 position is by the acyltransferase LYCAT, which controls the levels, acyl profile and function of phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2) (Bone et al. Mol Biol Cell 2017. 28:161-172). Here we examine how perturbation of LYCAT leads to a reduction in the levels of PI(4,5)P2 and phosphatidylinositol-3,4,5-trisphosphate (PI(3,4,5)P3). To measure the rate of PI(4,5)P2 synthesis, we treated cells with ionomycin to first ablate this PIP, followed by washout of the drug and monitoring of rate of reappearance via localization of a fluorescent PI(4,5)P2 probe. To measure the rate of PI(4,5)P2 degradation, we arrested PI(4,5)P2 synthesis by a pharmacological inhibitor, phenylarsine oxide (PAO) and monitored the loss of cellular PI(4,5)P2. Lastly, to examine the production of PI(3,4,5)P3, we treated cells with epidermal growth factor (EGF) and monitored the production of this PIP. Together, this work provides new information about how the dynamic and selective remodeling of specific phospholipids controls their levels, localization and function.

The Laryngeal Epithelium in Reflux

2011 ◽  
Vol 21 (3) ◽  
pp. 112-117 ◽  
Author(s):  
Elizabeth Erickson-Levendoski ◽  
Mahalakshmi Sivasankar
Keyword(s):  
Laryngopharyngeal Reflux ◽  
Critical Role ◽  
Structure And Function ◽  
Laryngeal Disease ◽  
Health And Disease ◽  
And Function ◽  
The Impact

The epithelium plays a critical role in the maintenance of laryngeal health. This is evident in that laryngeal disease may result when the integrity of the epithelium is compromised by insults such as laryngopharyngeal reflux. In this article, we will review the structure and function of the laryngeal epithelium and summarize the impact of laryngopharyngeal reflux on the epithelium. Research investigating the ramifications of reflux on the epithelium has improved our understanding of laryngeal disease associated with laryngopharyngeal reflux. It further highlights the need for continued research on the laryngeal epithelium in health and disease.

Recent Advances on Epidermal Growth Factor Receptor as a Molecular Target for Breast Cancer Therapeutics

2020 ◽  
Vol 21 ◽  
Author(s):  
Swathi R. Shetty ◽  
Ragini Yeeravalli ◽  
Tanya Bera ◽  
Amitava Das
Keyword(s):  
Breast Cancer ◽  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Tyrosine Kinase ◽  
Critical Role ◽  
Growth Factor Receptor ◽  
Type I ◽  
Egfr Inhibition ◽  
Epidermal Growth

: Epidermal growth factor receptor (EGFR), a type-I transmembrane protein with intrinsic tyrosine kinase activity is activated by peptide growth factors such as EGF, epigen, amphiregulin, etc. EGFR plays a vital role in regulating cell growth, migration, and differentiation in various tissue-specific cancers. It has been reported to be overexpressed in lung, head, and neck, colon, brain, pancreatic, and breast cancer that trigger tumor progression and drug resistance. EGFR overexpression alters the signaling pathway and induces cell division, invasion, and cell survival. Our prior studies demonstrated that EGFR inhibition modulates chemosensitivity in breast cancer stem cells thereby serving as a potential drug target for breast cancer mitigation. Tyrosine kinase inhibitors (Lapatinib, Neratinib) and monoclonal antibodies (Trastuzumab) targeting EGFR have been developed and approved by the US FDA for clinical use against breast cancer. This review highlights the critical role of EGFR in breast cancer progression and enumerates the various approaches being undertaken to inhibit aggressive breast cancers by suppressing the downstream pathways. Further, the mechanisms of action of potential molecules at various stages of drug development as well as clinically approved drugs for breast cancer treatment are illustrated.

scholarly journals The lung–gut axis during viral respiratory infections: the impact of gut dysbiosis on secondary disease outcomes

2021 ◽  
Author(s):  
Valentin Sencio ◽  
Marina Gomes Machado ◽  
François Trottein
Keyword(s):  
Gut Microbiota ◽  
Bacterial Infections ◽  
Respiratory Infections ◽  
Critical Role ◽  
Good Health ◽  
Disease Outcomes ◽  
And Function ◽  
Viral Respiratory Infections ◽  
The Impact ◽  
Viral Respiratory

AbstractBacteria that colonize the human gastrointestinal tract are essential for good health. The gut microbiota has a critical role in pulmonary immunity and host’s defense against viral respiratory infections. The gut microbiota’s composition and function can be profoundly affected in many disease settings, including acute infections, and these changes can aggravate the severity of the disease. Here, we discuss mechanisms by which the gut microbiota arms the lung to control viral respiratory infections. We summarize the impact of viral respiratory infections on the gut microbiota and discuss the potential mechanisms leading to alterations of gut microbiota’s composition and functions. We also discuss the effects of gut microbial imbalance on disease outcomes, including gastrointestinal disorders and secondary bacterial infections. Lastly, we discuss the potential role of the lung–gut axis in coronavirus disease 2019.

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