scholarly journals CNPase, a 2’,3’-Cyclic-nucleotide 3’-phosphodiesterase, as a Therapeutic Target to Attenuate Cardiac Hypertrophy by Enhancing Mitochondrial Energy Production

2021 ◽  
Vol 22 (19) ◽  
pp. 10806
Author(s):  
Keai Sinn Tan ◽  
Dongfang Wang ◽  
Ziqiang Lu ◽  
Yihan Zhang ◽  
Sixu Li ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Mitochondrial Respiration ◽  
Cyclic Nucleotide ◽  
Energy Production ◽  
Heart Diseases ◽  
Metabolic Stress ◽  
Nucleotide Metabolism ◽  
Atp Production ◽  
Mitochondrial Energy Production

Heart failure is the end-stage of all cardiovascular diseases with a ~25% 5-year survival rate, and insufficient mitochondrial energy production to meet myocardial demand is the hallmark of heart failure. Mitochondrial components involved in the regulation of ATP production remain to be fully elucidated. Recently, roles of 2′,3′-cyclic nucleotide-3′-phosphodiesterase (CNPase) in the pathophysiological processes of heart diseases have emerged, implicated by evidence that mitochondrial CNPase proteins are associated with mitochondrial integrity under metabolic stress. In this study, a zebrafish heart failure model was established, by employing antisense morpholino oligonucleotides and the CRISPR-Cas9 gene-editing system, which recapitulates heart failure phenotypes including heart dysfunction, pericardial edema, ventricular enlargement, bradycardia, and premature death. The translational implications of CNPase in the pathophysiological process of heart failure were tested in a pressure overload-induced heart hypertrophy model, which was carried out in rats through transverse abdominal aorta constriction (TAAC). AAV9-mediated myocardial delivery of CNPase mitigated the hypertrophic response through the specific hydrolysis of 2′-3′-cyclic nucleotides, supported by the decrease of cardiac hypertrophy and fibrosis, the integrity of mitochondrial ultrastructure, and indicators of heart contractility in the AAV9-TAAC group. Finally, the biometrics of a mitochondrial respiration assay carried out on a Seahorse cellular energy analyzer demonstrated that CNPase protects mitochondrial respiration and ATP production from AngII-induced metabolic stress. In summary, this study provides mechanistic insights into CNPase-2′,3′-cyclic nucleotide metabolism that protects the heart from energy starvation and suggests novel therapeutic approaches to treat heart failure by targeting CNPase activity.

scholarly journals Adaptive Changes in the Neuronal Proteome: Mitochondrial Energy Production, Endoplasmic Reticulum Stress, and Ribosomal Dysfunction in the Cellular Response to Metabolic Stress

2013 ◽  
Vol 33 (5) ◽  
pp. 673-683 ◽  
Author(s):  
Abigail G Herrmann ◽  
Ruth F Deighton ◽  
Thierry Le Bihan ◽  
Mailis C McCulloch ◽  
James L Searcy ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Energy Production ◽  
Cellular Response ◽  
Neuroblastoma Cell ◽  
Metabolic Stress ◽  
Human Neuroblastoma Cell ◽  
Electron Microscopic ◽  
Human Neuroblastoma ◽  
Metabolic Challenge ◽  
Mitochondrial Energy Production

Impaired energy metabolism in neurons is integral to a range of neurodegenerative diseases, from Alzheimer's disease to stroke. To investigate the complex molecular changes underpinning cellular adaptation to metabolic stress, we have defined the proteomic response of the SH-SY5Y human neuroblastoma cell line after exposure to a metabolic challenge of oxygen glucose deprivation (OGD) in vitro. A total of 958 proteins across multiple subcellular compartments were detected and quantified by label-free liquid chromatography mass spectrometry. The levels of 130 proteins were significantly increased ( P < 0.01) after OGD and the levels of 63 proteins were significantly decreased ( P < 0.01) while expression of the majority of proteins (765) was not altered. Network analysis identified novel protein–protein interactomes involved with mitochondrial energy production, protein folding, and protein degradation, indicative of coherent and integrated proteomic responses to the metabolic challenge. Approximately one third (61) of the differentially expressed proteins was associated with the endoplasmic reticulum and mitochondria. Electron microscopic analysis of these subcellular structures showed morphologic changes consistent with the identified proteomic alterations. Our investigation of the global cellular response to a metabolic challenge clearly shows the considerable adaptive capacity of the proteome to a slowly evolving metabolic challenge.

Abstract 97: Induction of Hexosamine Biosynthetic Pathway Promotes Cardiac Hypertrophy through Activation of O-GlcNAcylation

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Diem H Tran ◽  
Jianping Li ◽  
Xiaoding Wang ◽  
Herman I May ◽  
Gabriele G Schiattarella ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Biosynthetic Pathway ◽  
Heart Diseases ◽  
Pressure Overload ◽  
Neonatal Rat ◽  
Mice Model ◽  
Hexosamine Biosynthetic Pathway ◽  
Hypertrophic Growth

Background & significance: Heart failure affects approximately 6 million Americans, with 5-year survival of 50%, which is responsible for a huge burden on the US economy and healthcare system. The relevance and significance of the metabolic alteration to the pathogenesis of pressure overload-induced cardiac hypertrophy and heart failure are largely unknown. The hexosamine biosynthetic pathway (HBP) that is linked to metabolism of glucose, fatty acids and amino acids, has been implicated in the pathophysiology of heart diseases. Methods & results: Thoracic aortic constriction (TAC) was performed to induce heart failure by pressure overload in mice. At the in vitro levels, treatment of phenylephrine (PE, 50 μM) was used to induce cellular hypertrophy in neonatal rat ventricular myocytes (NRVM). Our data revealed that all the enzymes of the HBP were upregulated while induction of hypertrophy at both in vivo and in vitro levels. Consistently, the intermediate product of the HBP was elevated in heart by afterload stress, as measured by metabolomics analyses. In the transgenic mice model for Gfat1, the rate-limiting enzyme of the HBP, we found more profound cardiac hypertrophy and cardiac remodeling in response to pressure overload. The increase of O-GlcNAc was also observed. In addition, the regulation of O-GlcNAcylation by specific targeting of two enzymes of the HBP (1 mM Alloxan, an inhibitor of OGT and 10 μM PUGNAc, an inhibitor of OGA) in NRVM suggested an involvement of the mTOR signaling in the activation of O-GlcNAc levels and the hypertrophy response. Targeting of the HBP by either specific siRNA or Gfat1 inhibitor (Azaserine, 5 μM) led to decrease in cellular hypertrophic response. Conclusions: Together, our data strongly suggest that the HBP participates in cardiac hypertrophic growth and pharmacologic targeting of the HBP may represent a novel approach to ameliorate pathological remodeling.

scholarly journals Mitochondrial ATP production is required for endothelial cell control of vascular tone

2021 ◽  
Author(s):  
Calum Wilson ◽  
Matthew D. Lee ◽  
Charlotte Buckley ◽  
Xun Zhang ◽  
John G. McCarron
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Energy Production ◽  
Vascular Tone ◽  
Critical Role ◽  
Atp Synthesis ◽  
Tissue Perfusion ◽  
Atp Production ◽  
Mitochondrial Energy Production ◽  
Endothelial Control

AbstractArteries and veins are lined by non-proliferating endothelial cells that play a critical role in regulating blood flow. Endothelial cells also regulate tissue perfusion, metabolite exchange, and thrombosis. It is thought that endothelial cells rely on ATP generated via glycolysis to fuel each of these energy-demanding processes. However, endothelial metabolism has mainly been studied in the context of proliferative cells in angiogenesis, and little is known about energy production in endothelial cells within the fully-formed vascular wall. Using intact arteries isolated from rats and mice, we show that inhibiting mitochondrial oxidative phosphorylation disrupts endothelial control of vascular tone. The role for endothelial cell energy production is independent of species, sex, or vascular bed. Basal, mechanically-activated, and agonist-evoked calcium activity in intact artery endothelial cells are each prevented by inhibiting mitochondrial ATP synthesis. This effect is mimicked by blocking the transport of pyruvate, the master fuel for mitochondrial energy production, through the mitochondrial pyruvate carrier. These data show that mitochondrial ATP is necessary for calcium-dependent, nitric oxide mediated endothelial control of vascular tone, and identifies the critical role of endothelial mitochondrial energy production in fueling perfused blood vessel function.

Energy metabolism of preimplantation mammalian blastocysts

1983 ◽  
Vol 245 (1) ◽  
pp. C40-C45 ◽  
Author(s):  
D. J. Benos ◽  
R. S. Balaban
Keyword(s):  
Energy Consumption ◽  
Energy Metabolism ◽  
Total Energy ◽  
Mitochondrial Respiration ◽  
Energy Production ◽  
Na Transport ◽  
Total Energy Consumption ◽  
Atp Production ◽  
Transepithelial Na Transport ◽  
The Relationship

We have measured the relative contributions of glycolytic and oxidative energy production pathways of metabolism in rabbit and mouse preimplantation blastocysts. We have further studied the relationship between these pathways and active transepithelial Na+ transport. Our results show that over 85% of all ATP production arises from mitochondrial respiration. By using amphotericin B to increase the Na+ permeability of the apical (or uterine-facing) membrane of the blastocyst, we have determined that the ratio of ouabain-sensitive Na+ influx to ATP consumption is 3. Based on the measurements of ouabain-sensitive Na+ influx across blastocysts incubated in glucose-containing medium, only 6% of the total energy consumption of the embryo is used for active transepithelial Na+ transport.

scholarly journals Targeting muscle-enriched long non-coding RNA H19 reverses pathological cardiac hypertrophy

2020 ◽  
Author(s):  
Janika Viereck ◽  
Anne Bührke ◽  
Ariana Foinquinos ◽  
Shambhabi Chatterjee ◽  
Jan A Kleeberger ◽  
...  
Keyword(s):  
Heart Failure ◽  
Gene Therapy ◽  
Cardiac Hypertrophy ◽  
Therapeutic Potential ◽  
Heart Diseases ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Cardiac Remodelling ◽  
Large Animal ◽  
Pathological Cardiac Hypertrophy

Abstract Aims Pathological cardiac remodelling and subsequent heart failure represents an unmet clinical need. Long non-coding RNAs (lncRNAs) are emerging as crucial molecular orchestrators of disease processes, including that of heart diseases. Here, we report on the powerful therapeutic potential of the conserved lncRNA H19 in the treatment of pathological cardiac hypertrophy. Method and results Pressure overload-induced left ventricular cardiac remodelling revealed an up-regulation of H19 in the early phase but strong sustained repression upon reaching the decompensated phase of heart failure. The translational potential of H19 is highlighted by its repression in a large animal (pig) model of left ventricular hypertrophy, in diseased human heart samples, in human stem cell-derived cardiomyocytes and in human engineered heart tissue in response to afterload enhancement. Pressure overload-induced cardiac hypertrophy in H19 knock-out mice was aggravated compared to wild-type mice. In contrast, vector-based, cardiomyocyte-directed gene therapy using murine and human H19 strongly attenuated heart failure even when cardiac hypertrophy was already established. Mechanistically, using microarray, gene set enrichment analyses and Chromatin ImmunoPrecipitation DNA-Sequencing, we identified a link between H19 and pro-hypertrophic nuclear factor of activated T cells (NFAT) signalling. H19 physically interacts with the polycomb repressive complex 2 to suppress H3K27 tri-methylation of the anti-hypertrophic Tescalcin locus which in turn leads to reduced NFAT expression and activity. Conclusion H19 is highly conserved and down-regulated in failing hearts from mice, pigs and humans. H19 gene therapy prevents and reverses experimental pressure-overload-induced heart failure. H19 acts as an anti-hypertrophic lncRNA and represents a promising therapeutic target to combat pathological cardiac remodelling.

scholarly journals A Novel Role of Cyclic Nucleotide Phosphodiesterase 10A in Pathological Cardiac Remodeling and Dysfunction

Circulation ◽  
2020 ◽  
Vol 141 (3) ◽  
pp. 217-233 ◽  
Author(s):  
Si Chen ◽  
Yishuai Zhang ◽  
Janet K. Lighthouse ◽  
Deanne M. Mickelsen ◽  
Jiangbin Wu ◽  
...  
Keyword(s):  
Heart Failure ◽  
Angiotensin Ii ◽  
Growth Factor ◽  
Cardiac Hypertrophy ◽  
Cardiac Myocytes ◽  
Cardiac Remodeling ◽  
Cyclic Nucleotide ◽  
Cardiac Myocyte ◽  
Selective Inhibitor ◽  
Cardiovascular Biology

Background: Heart failure is a leading cause of death worldwide. Cyclic nucleotide phosphodiesterases (PDEs), through degradation of cyclic nucleotides, play critical roles in cardiovascular biology and disease. Our preliminary screening studies have revealed PDE10A upregulation in the diseased heart. However, the roles of PDE10A in cardiovascular biology and disease are largely uncharacterized. The current study is aimed to investigate the regulation and function of PDE10A in cardiac cells and in the progression of cardiac remodeling and dysfunction. Methods: We used isolated adult mouse cardiac myocytes and fibroblasts, as well as preclinical mouse models of hypertrophy and heart failure. The PDE10A selective inhibitor TP-10, and global PDE10A knock out mice were used. Results: We found that PDE10A expression remains relatively low in normal and exercised heart tissues. However, PDE10A is significantly upregulated in mouse and human failing hearts. In vitro, PDE10A deficiency or inhibiting PDE10A with selective inhibitor TP-10, attenuated cardiac myocyte pathological hypertrophy induced by Angiotensin II, phenylephrine, and isoproterenol, but did not affect cardiac myocyte physiological hypertrophy induced by IGF-1 (insulin-like growth factor 1). TP-10 also reduced TGF-β (transforming growth factor-β)–stimulated cardiac fibroblast activation, proliferation, migration and extracellular matrix synthesis. TP-10 treatment elevated both cAMP and cGMP levels in cardiac myocytes and cardiac fibroblasts, consistent with PDE10A as a cAMP/cGMP dual-specific PDE. In vivo, global PDE10A deficiency significantly attenuated myocardial hypertrophy, cardiac fibrosis, and dysfunction induced by chronic pressure overload via transverse aorta constriction or chronic neurohormonal stimulation via Angiotensin II infusion. Importantly, we demonstrated that the pharmacological effect of TP-10 is specifically through PDE10A inhibition. In addition, TP-10 is able to reverse pre-established cardiac hypertrophy and dysfunction. RNA-Sequencing and bioinformatics analysis further identified a PDE10A-regualted transcriptome involved in cardiac hypertrophy, fibrosis, and cardiomyopathy. Conclusions: Taken together, our study elucidates a novel role for PDE10A in the regulation of pathological cardiac remodeling and development of heart failure. Given that PDE10A has been proven to be a safe drug target, PDE10A inhibition may represent a novel therapeutic strategy for preventing and treating cardiac diseases associated with cardiac remodeling.

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