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Article ; Online: Opportunity "nox": a novel approach to preventing endothelial dysfunction in the context of insulin resistance.

Symons, J David

2013 Volume 62, Issue 6, Page(s) 1818–1820

MeSH term(s)	Animals ; Endothelial Cells/drug effects ; Insulin Resistance/physiology ; Male ; Membrane Glycoproteins/metabolism ; NADPH Oxidase 2 ; NADPH Oxidases/metabolism
Chemical Substances	Membrane Glycoproteins ; Cybb protein, mouse (EC 1.6.3.-) ; NADPH Oxidase 2 (EC 1.6.3.-) ; NADPH Oxidases (EC 1.6.3.-)
Language	English
Publishing date	2013-05-23
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Comment
ZDB-ID	80085-5
ISSN	1939-327X ; 0012-1797
ISSN (online)	1939-327X
ISSN	0012-1797
DOI	10.2337/db13-0255
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Article ; Online: Reduce, Reuse, Recycle, Run ! : 4 Rs to improve cardiac health in advanced age.

Cho, Jae Min / Ghosh, Rajeshwary / Mookherjee, Sohom / Boudina, Sihem / Symons, J David

Aging

2022 Volume 14, Issue 23, Page(s) 9388–9392

Abstract: During the aging process damaged/dysfunctional proteins and organelles accumulate and contribute to organ dysfunction. Luckily, there is a conserved intracellular process to reuse and recycle these dysregulated cellular components termed macroautophagy ( ... ...

Abstract	During the aging process damaged/dysfunctional proteins and organelles accumulate and contribute to organ dysfunction. Luckily, there is a conserved intracellular process to reuse and recycle these dysregulated cellular components termed macroautophagy (autophagy). Unfortunately, strong evidence indicates autophagy is compromised with aging, protein quality control is jeopardized, and resultant proteotoxicity can contribute significantly to age-associated organ dysfunction. Are there interventions that can re-establish autophagic flux that is otherwise impaired with aging? With particular regard to the heart, here we review evidence that caloric-restriction, the polyamine spermidine, and the mTOR inhibitor rapamycin, even when initiated late-in-life, restore cardiomyocyte autophagy to an extent that lessens age-associated cardiac dysfunction. Cho et al. provide a physiological intervention to this list i.e., regular physical exercise initiated late-in-life boosts cardiomyocyte autophagic flux and rejuvenates cardiac function in male mice. While this study provides strong evidence for a mechanism whereby heightened physical activity can lead to improved heart health in the context of aging, (i) only male mice were studied; (ii) the intensity of exercise-training might not be suitable for all; and (iii) mice with aging-associated comorbidities were not investigated. Nonetheless, Cho et al. provide robust evidence that a low-cost and simple behavioral intervention initiated late-in-life improves cardiomyocyte autophagic flux and rejuvenates cardiac function.
MeSH term(s)	Male ; Mice ; Animals ; Multiple Organ Failure/metabolism ; Myocytes, Cardiac/metabolism ; Aging/physiology ; Autophagy ; Spermidine/metabolism
Chemical Substances	Spermidine (U87FK77H25)
Language	English
Publishing date	2022-12-01
Publishing country	United States
Document type	Review ; Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ISSN	1945-4589
ISSN (online)	1945-4589
DOI	10.18632/aging.204415
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Article ; Online: Chaperone-mediated autophagy protects cardiomyocytes against hypoxic-cell death.

Ghosh, Rajeshwary / Gillaspie, Jennifer Jason / Campbell, Kenneth S / Symons, J David / Boudina, Sihem / Pattison, James Scott

American journal of physiology. Cell physiology

2022 Volume 323, Issue 5, Page(s) C1555–C1575

Abstract: Chaperone-mediated autophagy (CMA) is a chaperone-dependent process of selective cytosolic protein turnover that targets specific proteins to lysosomes for degradation. Enhancing protein degradation mechanisms has been shown to be beneficial in multiple ... ...

Abstract	Chaperone-mediated autophagy (CMA) is a chaperone-dependent process of selective cytosolic protein turnover that targets specific proteins to lysosomes for degradation. Enhancing protein degradation mechanisms has been shown to be beneficial in multiple models of cardiac disease, including myocardial infarction (MI) and ischemia-reperfusion (I/R) injury. However, the causal role of CMA in cardiomyocyte injury and death is largely unknown. Hypoxia is an important contributor to both MI and I/R damage, which are major, precedent causes of heart failure. Upregulating CMA was hypothesized to protect against hypoxia-induced cardiomyocyte death. Lysosome-associated membrane protein 2a (
MeSH term(s)	Humans ; Lysosomal-Associated Membrane Protein 2/genetics ; Lysosomal-Associated Membrane Protein 2/metabolism ; Myocytes, Cardiac/metabolism ; Chaperone-Mediated Autophagy ; Autophagy/genetics ; Lysosomes/metabolism ; Hypoxia/metabolism ; Apoptosis ; Heart Failure/metabolism
Chemical Substances	Lysosomal-Associated Membrane Protein 2 ; cobaltous chloride (EVS87XF13W)
Language	English
Publishing date	2022-05-18
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	392098-7
ISSN	1522-1563 ; 0363-6143
ISSN (online)	1522-1563
ISSN	0363-6143
DOI	10.1152/ajpcell.00369.2021
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Article: A Fluorogenic-Based Assay to Measure Chaperone-Mediated Autophagic Activity in Cells and Tissues.

Jonnavithula, Anila / Tandar, Megan / Umar, Mohammed / Orton, Scott N / Woodrum, MacKenzie C / Mookherjee, Sohom / Boudina, Sihem / Symons, J David / Ghosh, Rajeshwary

bioRxiv : the preprint server for biology

2023

Language	English
Publishing date	2023-12-15
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.12.14.571785
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Article ; Online: Sequestosome 1 (p62) mitigates hypoxia-induced cardiac dysfunction by stabilizing hypoxia-inducible factor 1α and nuclear factor erythroid 2-related factor 2.

Ghosh, Rajeshwary / Fatahian, Amir Nima / Rouzbehani, Omid M T / Hathaway, Marissa A / Mosleh, Tariq / Vinod, Vishaka / Vowles, Sidney / Stephens, Sophie L / Chung, Siu-Lai Desmond / Cao, Isaac D / Jonnavithula, Anila / Symons, J David / Boudina, Sihem

Cardiovascular research

2024 Volume 120, Issue 5, Page(s) 531–547

Abstract: Aims: Heart failure due to ischaemic heart disease (IHD) is a leading cause of mortality worldwide. A major contributing factor to IHD-induced cardiac damage is hypoxia. Sequestosome 1 (p62) is a multi-functional adaptor protein with pleiotropic roles ... ...

Abstract	Aims: Heart failure due to ischaemic heart disease (IHD) is a leading cause of mortality worldwide. A major contributing factor to IHD-induced cardiac damage is hypoxia. Sequestosome 1 (p62) is a multi-functional adaptor protein with pleiotropic roles in autophagy, proteostasis, inflammation, and cancer. Despite abundant expression in cardiomyocytes, the role of p62 in cardiac physiology is not well understood. We hypothesized that cardiomyocyte-specific p62 deletion evokes hypoxia-induced cardiac pathology by impairing hypoxia-inducible factor 1α (Hif-1α) and nuclear factor erythroid 2-related factor 2 (Nrf2) signalling. Methods and results: Adult mice with germline deletion of cardiomyocyte p62 exhibited mild cardiac dysfunction under normoxic conditions. Transcriptomic analyses revealed a selective impairment in Nrf2 target genes in the hearts from these mice. Demonstrating the functional importance of this adaptor protein, adult mice with inducible depletion of cardiomyocyte p62 displayed hypoxia-induced contractile dysfunction, oxidative stress, and cell death. Mechanistically, p62-depleted hearts exhibit impaired Hif-1α and Nrf2 transcriptional activity. Because findings from these two murine models suggested a cardioprotective role for p62, mechanisms were evaluated using H9c2 cardiomyoblasts. Loss of p62 in H9c2 cells exposed to hypoxia reduced Hif-1α and Nrf2 protein levels. Further, the lack of p62 decreased Nrf2 protein expression, nuclear translocation, and transcriptional activity. Repressed Nrf2 activity associated with heightened Nrf2-Keap1 co-localization in p62-deficient cells, which was concurrent with increased Nrf2 ubiquitination facilitated by the E3 ligase Cullin 3, followed by proteasomal-mediated degradation. Substantiating our results, a gain of p62 in H9c2 cells stabilized Nrf2 and increased the transcriptional activity of Nrf2 downstream targets. Conclusion: Cardiac p62 mitigates hypoxia-induced cardiac dysfunction by stabilizing Hif-1α and Nrf2.
MeSH term(s)	Animals ; Sequestosome-1 Protein/metabolism ; Sequestosome-1 Protein/genetics ; NF-E2-Related Factor 2/metabolism ; NF-E2-Related Factor 2/genetics ; NF-E2-Related Factor 2/deficiency ; Myocytes, Cardiac/metabolism ; Myocytes, Cardiac/pathology ; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism ; Hypoxia-Inducible Factor 1, alpha Subunit/genetics ; Signal Transduction ; Oxidative Stress ; Mice, Knockout ; Disease Models, Animal ; Kelch-Like ECH-Associated Protein 1/metabolism ; Kelch-Like ECH-Associated Protein 1/genetics ; Protein Stability ; Cell Hypoxia ; Ubiquitination ; Cell Line ; Mice, Inbred C57BL ; Male
Chemical Substances	Sequestosome-1 Protein ; NF-E2-Related Factor 2 ; Sqstm1 protein, mouse ; Hif1a protein, mouse ; Hypoxia-Inducible Factor 1, alpha Subunit ; Nfe2l2 protein, mouse ; Kelch-Like ECH-Associated Protein 1 ; Keap1 protein, mouse
Language	English
Publishing date	2024-02-09
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	80340-6
ISSN	1755-3245 ; 0008-6363
ISSN (online)	1755-3245
ISSN	0008-6363
DOI	10.1093/cvr/cvae023
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Zs.A 565: Show issues

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Article ; Online: Protein and Mitochondria Quality Control Mechanisms and Cardiac Aging.

Ghosh, Rajeshwary / Vinod, Vishaka / Symons, J David / Boudina, Sihem

Cells

2020 Volume 9, Issue 4

Abstract: Cardiovascular disease (CVD) is the number one cause of death in the United States. Advancing age is a primary risk factor for developing CVD. Estimates indicate that 20% of the US population will be ≥65 years old by 2030. Direct expenditures for ... ...

Abstract	Cardiovascular disease (CVD) is the number one cause of death in the United States. Advancing age is a primary risk factor for developing CVD. Estimates indicate that 20% of the US population will be ≥65 years old by 2030. Direct expenditures for treating CVD in the older population combined with indirect costs, secondary to lost wages, are predicted to reach $1.1 trillion by 2035. Therefore, there is an eminent need to discover novel therapeutic targets and identify new interventions to delay, lessen the severity, or prevent cardiovascular complications associated with advanced age. Protein and organelle quality control pathways including autophagy/lysosomal and the ubiquitin-proteasome systems, are emerging contributors of age-associated myocardial dysfunction. In general, two findings have sparked this interest. First, strong evidence indicates that cardiac protein degradation pathways are altered in the heart with aging. Second, it is well accepted that damaged and misfolded protein aggregates and dysfunctional mitochondria accumulate in the heart with age. In this review, we will: (i) define the different protein and mitochondria quality control mechanisms in the heart; (ii) provide evidence that each quality control pathway becomes dysfunctional during cardiac aging; and (iii) discuss current advances in targeting these pathways to maintain cardiac function with age.
MeSH term(s)	Age Factors ; Aged ; Aged, 80 and over ; Animals ; Autophagy/physiology ; Cardiovascular Diseases/metabolism ; Cardiovascular Diseases/pathology ; Humans ; Mice ; Mitochondria, Heart/metabolism ; Mitochondrial Proteins/metabolism ; Mitophagy/physiology ; Proteolysis ; Quality Control
Chemical Substances	Mitochondrial Proteins
Language	English
Publishing date	2020-04-10
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells9040933
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Article ; Online: Vasoreactivity of the Murine External Jugular Vein and Carotid Artery.

Cho, Jae Min / Shiu, Yan-Ting / Symons, J David / Lee, Timmy

Journal of vascular research

2020 Volume 57, Issue 5, Page(s) 291–301

Abstract: Introduction: Impaired venous reactivity has potential to contribute to clinically significant pathologies such as arteriovenous fistula (AVF) maturation failure. Vascular segments commonly used in murine preclinical models of AVF include the carotid ... ...

Abstract	Introduction: Impaired venous reactivity has potential to contribute to clinically significant pathologies such as arteriovenous fistula (AVF) maturation failure. Vascular segments commonly used in murine preclinical models of AVF include the carotid artery and external jugular vein. Detailed descriptions of isometric procedures to evaluate function of murine external jugular vein ex vivo have not been previously published. Objective: To establish isometric procedures to measure naive murine external jugular vein reactivity ex vivo. Methods: Vasomotor responses of external jugular veins and ipsilateral common carotid arteries from C57BL/6 mice were evaluated using isometric tension procedures. Results: External jugular veins developed tension (p < 0.05) to potassium chloride and U-46619, but not to phenylephrine, whereas common carotid arteries responded to all 3 agents (p < 0.05). While maximal responses to acetylcholine (ACh) were similar between the venous and arterial segments, the dose required to achieve this value was lower (p < 0.05) in the artery versus vein. Nitric oxide synthase inhibition attenuated (p < 0.05) but did not abolish ACh-evoked vasorelaxation in both vascular segments, whereas cyclooxygenase blockade had no effect. Endothelium-independent vasorelaxation to sodium nitroprusside was similar in the artery and vein. Conclusion: Vasorelaxation and vasocontraction can be reliably assessed in the external jugular vein in C57BL/6 mice using isometric procedures.
MeSH term(s)	Animals ; Carotid Artery, Common/drug effects ; Carotid Artery, Common/metabolism ; Carotid Artery, Common/physiology ; Endothelium, Vascular/drug effects ; Endothelium, Vascular/metabolism ; Endothelium, Vascular/physiology ; Jugular Veins/drug effects ; Jugular Veins/metabolism ; Jugular Veins/physiology ; Male ; Mice, Inbred C57BL ; Muscle, Smooth, Vascular/drug effects ; Muscle, Smooth, Vascular/metabolism ; Muscle, Smooth, Vascular/physiology ; Myography ; Nitric Oxide/metabolism ; Nitric Oxide Synthase Type III/metabolism ; Prostaglandins/metabolism ; Receptors, Adrenergic, alpha-1/metabolism ; Vasoconstriction/drug effects ; Vasoconstrictor Agents/pharmacology ; Vasodilation/drug effects ; Vasodilator Agents/pharmacology
Chemical Substances	Prostaglandins ; Receptors, Adrenergic, alpha-1 ; Vasoconstrictor Agents ; Vasodilator Agents ; Nitric Oxide (31C4KY9ESH) ; Nitric Oxide Synthase Type III (EC 1.14.13.39) ; Nos3 protein, mouse (EC 1.14.13.39)
Language	English
Publishing date	2020-06-15
Publishing country	Switzerland
Document type	Comparative Study ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	1105259-4
ISSN	1423-0135 ; 1018-1172
ISSN (online)	1423-0135
ISSN	1018-1172
DOI	10.1159/000508129
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Article ; Online: Ceramides and other sphingolipids as drivers of cardiovascular disease.

Choi, Ran Hee / Tatum, Sean M / Symons, J David / Summers, Scott A / Holland, William L

Nature reviews. Cardiology

2021 Volume 18, Issue 10, Page(s) 701–711

Abstract: Increases in calorie consumption and sedentary lifestyles are fuelling a global pandemic of cardiometabolic diseases, including coronary artery disease, diabetes mellitus, cardiomyopathy and heart failure. These lifestyle factors, when combined with ... ...

Abstract	Increases in calorie consumption and sedentary lifestyles are fuelling a global pandemic of cardiometabolic diseases, including coronary artery disease, diabetes mellitus, cardiomyopathy and heart failure. These lifestyle factors, when combined with genetic predispositions, increase the levels of circulating lipids, which can accumulate in non-adipose tissues, including blood vessel walls and the heart. The metabolism of these lipids produces bioactive intermediates that disrupt cellular function and survival. A compelling body of evidence suggests that sphingolipids, such as ceramides, account for much of the tissue damage in these cardiometabolic diseases. In humans, serum ceramide levels are proving to be accurate biomarkers of adverse cardiovascular disease outcomes. In mice and rats, pharmacological inhibition or depletion of enzymes driving de novo ceramide synthesis prevents the development of diabetes, atherosclerosis, hypertension and heart failure. In cultured cells and isolated tissues, ceramides perturb mitochondrial function, block fuel usage, disrupt vasodilatation and promote apoptosis. In this Review, we discuss the body of literature suggesting that ceramides are drivers - and not merely passengers - on the road to cardiovascular disease. Moreover, we explore the feasibility of therapeutic strategies to lower ceramide levels to improve cardiovascular health.
MeSH term(s)	Animals ; Cardiovascular Diseases/epidemiology ; Ceramides/metabolism ; Mice ; Rats ; Sphingolipids/metabolism
Chemical Substances	Ceramides ; Sphingolipids
Language	English
Publishing date	2021-03-26
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2490375-9
ISSN	1759-5010 ; 1759-5002
ISSN (online)	1759-5010
ISSN	1759-5002
DOI	10.1038/s41569-021-00536-1
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Zs.MG 98: Show issues

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Article ; Online: Soluble (pro)renin receptor as a potential therapy for diabetes insipidus.

Yang, Kevin T / Yang, Tianxin / Symons, J David

American journal of physiology. Renal physiology

2018 Volume 315, Issue 5, Page(s) F1416–F1421

Abstract: The antidiuretic hormone vasopressin (VP) is produced by the hypothalamus and is stored and secreted from the posterior pituitary. VP acts via VP type 2 receptors (V2Rs) on the basolateral membrane of principal cells of the collecting duct (CD) to ... ...

Abstract	The antidiuretic hormone vasopressin (VP) is produced by the hypothalamus and is stored and secreted from the posterior pituitary. VP acts via VP type 2 receptors (V2Rs) on the basolateral membrane of principal cells of the collecting duct (CD) to regulate fluid permeability. The VP-evoked endocrine pathway is essential in determining urine concentrating capability. For example, a defect in any component of the VP signaling pathway can result in polyuria, polydipsia, and hypotonic urine, collectively termed diabetes insipidus (DI). A lack of VP production precipitates central diabetes insipidus (CDI), which can be managed effectively by VP supplementation. A majority of cases of nephrogenic diabetes insipidus (NDI) result from V2R mutations that impair receptor sensitivity. No specific therapy is currently available for management of NDI. Evidence is evolving that (pro)renin receptor (PRR), a newly identified member of the renin-angiotensin system, is capable of regulating VP production and action. As such, PRR should be considered strongly as a therapeutic target for treating CDI and NDI. The current review will summarize recent advances in understanding the physiology of renal and central PRR as it relates to the two types of DI.
MeSH term(s)	Animals ; Antidiuretic Agents/therapeutic use ; Diabetes Insipidus/drug therapy ; Diabetes Insipidus/enzymology ; Diabetes Insipidus/physiopathology ; Diuresis/drug effects ; Genetic Predisposition to Disease ; Humans ; Kidney/drug effects ; Kidney/enzymology ; Kidney/pathology ; Mutation ; Phenotype ; Receptors, Cell Surface/metabolism ; Receptors, Cell Surface/therapeutic use ; Receptors, Vasopressin/genetics ; Renin-Angiotensin System/drug effects ; Vasopressins/metabolism
Chemical Substances	AVPR2 protein, human ; Antidiuretic Agents ; Receptors, Cell Surface ; Receptors, Vasopressin ; prorenin receptor ; Vasopressins (11000-17-2)
Language	English
Publishing date	2018-07-18
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S. ; Review
ZDB-ID	603837-2
ISSN	1522-1466 ; 0363-6127
ISSN (online)	1522-1466
ISSN	0363-6127
DOI	10.1152/ajprenal.00266.2018
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Article ; Online: Cardiac gene therapy treats diabetic cardiomyopathy and lowers blood glucose.

Li, Jing / Richmond, Bradley / Cluntun, Ahmad A / Bia, Ryan / Walsh, Maureen A / Shaw, Kikuyo / Symons, J David / Franklin, Sarah / Rutter, Jared / Funai, Katsuhiko / Shaw, Robin M / Hong, TingTing

JCI insight

2023 Volume 8, Issue 18

Abstract: Diabetic cardiomyopathy, an increasingly global epidemic and a major cause of heart failure with preserved ejection fraction (HFpEF), is associated with hyperglycemia, insulin resistance, and intracardiomyocyte calcium mishandling. Here we identify that, ...

Abstract	Diabetic cardiomyopathy, an increasingly global epidemic and a major cause of heart failure with preserved ejection fraction (HFpEF), is associated with hyperglycemia, insulin resistance, and intracardiomyocyte calcium mishandling. Here we identify that, in db/db mice with type 2 diabetes-induced HFpEF, abnormal remodeling of cardiomyocyte transverse-tubule microdomains occurs with downregulation of the membrane scaffolding protein cardiac bridging integrator 1 (cBIN1). Transduction of cBIN1 by AAV9 gene therapy can restore transverse-tubule microdomains to normalize intracellular distribution of calcium-handling proteins and, surprisingly, glucose transporter 4 (GLUT4). Cardiac proteomics revealed that AAV9-cBIN1 normalized components of calcium handling and GLUT4 translocation machineries. Functional studies further identified that AAV9-cBIN1 normalized insulin-dependent glucose uptake in diabetic cardiomyocytes. Phenotypically, AAV9-cBIN1 rescued cardiac lusitropy, improved exercise intolerance, and ameliorated hyperglycemia in diabetic mice. Restoration of transverse-tubule microdomains can improve cardiac function in the setting of diabetic cardiomyopathy and can also improve systemic glycemic control.
MeSH term(s)	Animals ; Mice ; Blood Glucose ; Diabetic Cardiomyopathies/genetics ; Diabetic Cardiomyopathies/therapy ; Heart Failure/therapy ; Calcium ; Diabetes Mellitus, Experimental/complications ; Diabetes Mellitus, Experimental/therapy ; Diabetes Mellitus, Type 2/complications ; Diabetes Mellitus, Type 2/therapy ; Stroke Volume ; Anti-Arrhythmia Agents ; Cardiotonic Agents ; Myocytes, Cardiac ; Hyperglycemia/therapy ; Adaptor Proteins, Signal Transducing ; Amino Acids ; Enzyme Inhibitors ; Genetic Therapy
Chemical Substances	Blood Glucose ; Calcium (SY7Q814VUP) ; Anti-Arrhythmia Agents ; Cardiotonic Agents ; Adaptor Proteins, Signal Transducing ; Amino Acids ; Enzyme Inhibitors
Language	English
Publishing date	2023-09-22
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ISSN	2379-3708
ISSN (online)	2379-3708
DOI	10.1172/jci.insight.166713
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