scholarly journals Hypoxia-Inducible Factor-Dependent Degeneration, Failure, and Malignant Transformation of the Heart in the Absence of the von Hippel-Lindau Protein

2008 ◽  
Vol 28 (11) ◽  
pp. 3790-3803 ◽  
Author(s):  
Li Lei ◽  
Steve Mason ◽  
Dinggang Liu ◽  
Yan Huang ◽  
Carolyn Marks ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Myocyte ◽  
Hypoxia Inducible Factor ◽  
Premature Death ◽  
Cardiac Tumors ◽  
Human Heart Failure ◽  
Von Hippel Lindau ◽  
Chronic Activation ◽  
Hif Pathway ◽  
Transcription Factor 1

ABSTRACT Hypoxia-inducible transcription factor 1 (HIF-1) and HIF-2α regulate the expression of an expansive array of genes associated with cellular responses to hypoxia. Although HIF-regulated genes mediate crucial beneficial short-term biological adaptations, we hypothesized that chronic activation of the HIF pathway in cardiac muscle, as occurs in advanced ischemic heart disease, is detrimental. We generated mice with cardiac myocyte-specific deletion of the von Hippel-Lindau protein (VHL), an essential component of an E3 ubiquitin ligase responsible for suppressing HIF levels during normoxia. These mice were born at expected frequency and thrived until after 3 months postbirth, when they developed severe progressive heart failure and premature death. VHL-null hearts developed lipid accumulation, myofibril rarefaction, altered nuclear morphology, myocyte loss, and fibrosis, features seen for various forms of human heart failure. Further, nearly 50% of VHL−/− hearts developed malignant cardiac tumors with features of rhabdomyosarcoma and the capacity to metastasize. As compelling evidence for the mechanistic contribution of HIF-1α, the concomitant deletion of VHL and HIF-1α in the heart prevented this phenotype and restored normal longevity. These findings strongly suggest that chronic activation of the HIF pathway in ischemic hearts is maladaptive and contributes to cardiac degeneration and progression to heart failure.

scholarly journals Cardiopulmonary function in two human disorders of the hypoxia‐inducible factor (HIF) pathway: von Hippel‐Lindau disease and HIF‐2α gain‐of‐function mutation

2011 ◽  
Vol 25 (6) ◽  
pp. 2001-2011 ◽  
Author(s):  
Federico Formenti ◽  
Philip A. Beer ◽  
Quentin P. P. Croft ◽  
Keith L. Dorrington ◽  
Daniel P. Gale ◽  
...  
Keyword(s):  
Hypoxia Inducible Factor ◽  
Gain Of Function ◽  
Cardiopulmonary Function ◽  
Von Hippel Lindau ◽  
Human Disorders ◽  
Von Hippel Lindau Disease ◽  
Hif Pathway

Decreased expression of hypoxia-inducible factor 1 in human heart failure

2007 ◽  
Vol 2007 (Fall) ◽  
Author(s):  
Thomas F Solbach ◽  
Alexander Weidemann ◽  
Martin F Fromm ◽  
Oliver Zolk
Keyword(s):  
Heart Failure ◽  
Human Heart ◽  
Hypoxia Inducible Factor ◽  
Human Heart Failure ◽  
Hypoxia Inducible Factor 1

Abstract 12646: Oxidation-Dependent Phosphomimetic Effect of a Human Heart Failure Mutation of Phospholamban

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Neha Abrol ◽  
Pieter P de Tombe ◽  
Seth L Robia
Keyword(s):  
Heart Failure ◽  
Molecular Mechanism ◽  
Fluorescent Protein ◽  
Resonance Energy ◽  
Premature Death ◽  
Oxidative Modification ◽  
Live Cells ◽  
Adrenergic Stimulation ◽  
Cysteine Oxidation ◽  
Human Heart Failure

Rationale: A naturally-occurring, missense Arg9-to-Cys (R9C) mutation of phospholamban (PLB) triggers cardiomyopathy and premature death in humans. However, the fundamental molecular mechanism underlying the cardiotoxic role of R9C-PLB in sarco/endoplasmic reticulum Ca 2+ -ATPase (SERCA) regulation and cardiomyocyte Ca 2+ handling is not clear. Objective: The goal of this study was to investigate the acute physiological consequences of R9C-PLB mutation on cardiomyocyte Ca 2+ kinetics and contractility and identify the molecular mechanism underlying R9C pathology. Methods and Results: We measured the physiological consequences of R9C-PLB mutation on Ca 2+ transients and sarcomere shortening in adult cardiomyocytes at increasing pacing frequencies. In contrast to studies of chronic R9C-PLB expression in transgenic mice, we found that acute expression of R9C-PLB exerts a positively inotropic and lusitropic effect in cardiomyocytes. Importantly, R9C-PLB exhibited blunted sensitivity to frequency potentiation and β-adrenergic stimulation, two major physiological mechanisms for the regulation of cardiac performance. To identify the molecular mechanism of R9C pathology, we fused fluorescent protein tags to PLB and SERCA, and compared the effect of R9C and pentamer-destabilizing mutation (SSS) on PLB oligomerization and PLB-SERCA interaction. Fluorescence resonance energy transfer (FRET) measurements in live cells revealed that R9C exhibited an increased affinity of PLB oligomerization, and a decreased binding affinity to SERCA due to an oxidative modification which mimics phosphorylation. Real-time FRET analysis in cardiomyocytes revealed that R9C-PLB exhibits enhanced sensitivity to oxidative stress, which is a prevailing condition in heart failure. Conclusions: We conclude that the primary mechanism of R9C pathology is a phosphomimetic effect of PLB cysteine oxidation, manifested as increased oligomerization and a change in the structure of the PLB-SERCA regulatory complex.

scholarly journals HIF Pathways in Clear Cell Renal Cancer

2021 ◽  
Author(s):  
Olivia Lombardi ◽  
David Robert Mole
Keyword(s):  
Cell Proliferation ◽  
Clear Cell ◽  
Hypoxia Inducible Factor ◽  
Von Hippel Lindau ◽  
Pathway Activation ◽  
Cellular Energetics ◽  
Cellular Oxygen ◽  
Immune Destruction ◽  
Hif Pathway ◽  
Cell Renal Cancer

Clear cell renal cancers (ccRCC) are characterized by inactivation of the VHL (von Hippel–Lindau) tumor suppressor. Work leading to the 2019 Nobel Prize for Physiology or Medicine has shown that this is central to cellular oxygen-sensing, orchestrated by the HIF (hypoxia-inducible factor) transcription factors. These regulate hundreds of genes that underpin many hallmarks of cancer, including angiogenesis, cellular energetics, cell proliferation, resisting cell death, and avoiding immune destruction. However, HIF also promotes processes that are detrimental to cancer cells. Therefore, the overall consequence of HIF pathway activation is a balance of these influences. We explore how variations in the HIF pathway during tumorigenesis alter this balance to promote ccRCC formation.

scholarly journals The von Hippel Lindau/Hypoxia-inducible Factor (HIF) Pathway Regulates the Transcription of the HIF-Proline Hydroxylase Genes in Response to Low Oxygen

2003 ◽  
Vol 278 (49) ◽  
pp. 48690-48695 ◽  
Author(s):  
Luis del Peso ◽  
María C. Castellanos ◽  
Elisa Temes ◽  
Silvia Martín-Puig ◽  
Yolanda Cuevas ◽  
...  
Keyword(s):  
Hypoxia Inducible Factor ◽  
Low Oxygen ◽  
Von Hippel Lindau ◽  
Hif Pathway ◽  
Proline Hydroxylase

scholarly journals Co-incidence of RCC-susceptibility polymorphisms with HIF cis-acting sequences supports a pathway tuning model of cancer

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Virginia Schmid ◽  
Veronique N. Lafleur ◽  
Olivia Lombardi ◽  
Ran Li ◽  
Rafik Salama ◽  
...  
Keyword(s):  
Cancer Susceptibility ◽  
Association Studies ◽  
Hypoxia Inducible Factor ◽  
Genome Wide Association Studies ◽  
Cis Acting ◽  
Von Hippel Lindau ◽  
Selective Pressures ◽  
Oncogenic Pathways ◽  
Genome Wide ◽  
Hif Pathway

AbstractEmerging evidence suggests that dysregulation of oncogenic pathways requires precise tuning in order for cancer to develop. To test this, we examined the overlap between cis-acting elements of the hypoxia-inducible factor (HIF) pathway and cancer-susceptibility polymorphisms as defined in genome-wide association studies (GWAS). In renal cancer, where HIF is constitutively and un-physiologically activated by mutation of the von Hippel-Lindau tumour suppressor, we observed marked excess overlap, which extended to potential susceptibility polymorphisms that are below the conventional threshold applied in GWAS. In contrast, in other cancers where HIF is upregulated by different mechanisms, including micro-environmental hypoxia, we observed no excess in overlap. Our findings support a ‘pathway tuning’ model of cancer, whereby precise modulation of multiple outputs of specific, activated pathways is important in oncogenesis. This implies that selective pressures to modulate such pathways operate during cancer development and should focus attempts to identify their nature and consequences.

scholarly journals pVHL Modification by NEDD8 Is Required for Fibronectin Matrix Assembly and Suppression of Tumor Development

2004 ◽  
Vol 24 (8) ◽  
pp. 3251-3261 ◽  
Author(s):  
Natalie H. Stickle ◽  
Jacky Chung ◽  
Jeffery M. Klco ◽  
Richard P. Hill ◽  
William G. Kaelin ◽  
...  
Keyword(s):  
Hypoxia Inducible Factor ◽  
Tumor Development ◽  
Three Dimensional ◽  
Suppressor Gene ◽  
Matrix Assembly ◽  
Von Hippel Lindau ◽  
Fibronectin Matrix ◽  
Matrix Expression ◽  
Vhl Disease ◽  
Hif Pathway

ABSTRACT Functional inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene is the cause of the familial VHL disease and most sporadic renal clear-cell carcinomas (RCC). pVHL has been shown to play a role in the destruction of hypoxia-inducible factor α (HIF-α) subunits via ubiquitin-mediated proteolysis and in the regulation of fibronectin matrix assembly. Although most disease-causing pVHL mutations hinder the regulation of the HIF pathway, every disease-causing pVHL mutant tested to date has failed to promote the assembly of the fibronectin matrix, underscoring its potential importance in VHL disease. Here, we report that a ubiquitin-like molecule called NEDD8 covalently modifies pVHL. A nonneddylateable pVHL mutant, while retaining its ability to ubiquitylate HIF, failed to bind to and promote the assembly of the fibronectin matrix. Expression of the neddylation-defective pVHL in RCC cells, while restoring the regulation of HIF, failed to promote the differentiated morphology in a three-dimensional growth assay and was insufficient to suppress the formation of tumors in SCID mice. These results suggest that NEDD8 modification of pVHL plays an important role in fibronectin matrix assembly and that in the absence of such regulation, an intact HIF pathway is insufficient to prevent VHL-associated tumorigenesis.

scholarly journals Repression of Pdzrn3 is required for heart maturation and protects against heart failure

2020 ◽  
Author(s):  
Mathieu Pernot ◽  
Béatrice Jaspard-vinassa ◽  
Alice Abelanet ◽  
Sebastien Rubin ◽  
Isabelle Forfar ◽  
...  
Keyword(s):  
Heart Failure ◽  
Contractile Function ◽  
Protein Complexes ◽  
Premature Death ◽  
Electric Signal ◽  
Causative Role ◽  
Human Heart Failure ◽  
Mechanical Coupling ◽  
Over Expression ◽  
Anisotropic Conduction

AbstractHeart failure is the final common stage of most cardiopathies. Cardiomyocytes connect with others via their extremities by intercalated disk protein complexes. This planar and directional organization of myocytes is crucial for mechanical coupling and anisotropic conduction of the electric signal in the heart. One of the hallmarks of heart failure is alterations in the contact sites between cardiomyocytes. Yet no factor on its own is known to coordinate cardiomyocyte polarized organization. We report enhanced levels of an ubiquitine ligase Pdzrn3 in diseased hypertrophic human and mouse myocardium, which correlates with a loss of cardiomyocyte polarized elongation. We provide evidence that Pdzrn3 has a causative role in heart failure. We found that cardiac Pdzrn3 deficiency protected against heart failure while over expression of Pdzrn3 in mouse cardiomyocytes during the first weeks of life, impaired postnatal cardiomyocyte maturation leading to premature death. Our results reveal a novel signaling pathway that controls a genetic program essential for heart maturation and maintenance of overall geometry, as well as the contractile function of cardiomyocytes, and implicates PDZRN3 as a potential therapeutic target for the prevention of human heart failure.

scholarly journals Systematic evaluation of the association between hemoglobin levels and metabolic profile implicates beneficial effects of hypoxia

2021 ◽  
Vol 7 (29) ◽  
pp. eabi4822
Author(s):  
Juha Auvinen ◽  
Joona Tapio ◽  
Ville Karhunen ◽  
Johannes Kettunen ◽  
Raisa Serpi ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Target Genes ◽  
Hypoxia Inducible Factor ◽  
Liver Weight ◽  
Systematic Evaluation ◽  
Metabolic Profiles ◽  
Beneficial Effects ◽  
Chronic Activation ◽  
Surrogate Measure ◽  
Hif Pathway

Activation of the hypoxia-inducible factor (HIF) pathway reprograms energy metabolism. Hemoglobin (Hb) is the main carrier of oxygen. Using its normal variation as a surrogate measure for hypoxia, we explored whether lower Hb levels could lead to healthier metabolic profiles in mice and humans (n = 7175) and used Mendelian randomization (MR) to evaluate potential causality (n = 173,480). The results showed evidence for lower Hb levels being associated with lower body mass index, better glucose tolerance and other metabolic profiles, lower inflammatory load, and blood pressure. Expression of the key HIF target genes SLC2A4 and Slc2a1 in skeletal muscle and adipose tissue, respectively, associated with systolic blood pressure in MR analyses and body weight, liver weight, and adiposity in mice. Last, manipulation of murine Hb levels mediated changes to key metabolic parameters. In conclusion, low-end normal Hb levels may be favorable for metabolic health involving mild chronic activation of the HIF response.

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