Abstract 17345: Dysregulated Phenylalanine Catabolism is a Key Determinant of Cardiac Aging

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Gabor Czibik
Keyword(s):  
Cellular Senescence ◽  
Cardiac Dysfunction ◽  
Interstitial Fibrosis ◽  
Cardiomyocyte Hypertrophy ◽  
Cardiac Aging ◽  
Human Cardiomyocytes ◽  
Redox Biology ◽  
Age Related ◽  
The Impact

Introduction: Cardiac aging is characterized by cardiomyocyte hypertrophy and myocardial interstitial fibrosis with impaired contractility and relaxation. Recent metabolomics studies revealed an age-dependent increase in the plasma levels of essential amino acid phenylalanine (Phe), which is predictive of heart failure hospitalization. The present study aimed to dissect 1) the basis for increased Phe levels with age and 2) how Phe may promote age-related cardiac dysfunction. Methods: To establish a role for Phe in driving cardiac aging, wild-type (WT) male mice were treated twice a day with Phe (200 mg/kg) for a month. The impact of Phe on cellular senescence, redox biology and epigenetics were explored in cultured cardiomyocytes (primary adult rat and AC-16 human cardiomyocytes) treated with Phe. In vivo cardiac structure and function, together with Phe catabolism were monitored in WT and in p21 -/- mice (in pursuit of p21 induction with Phe and age) up to 24 months of age. Finally, we treated aged WT mice with tetrahydrobiopterin (BH4; 10 mg/kg), the essential cofactor for Phe-degrading enzyme phenylalanine hydroxylase (Pah). The effect of aging and Phe treatment on hepatic Phe catabolism was explored in vivo and vitro in AML-12 hepatocytes. Results: Natural aging induced a progressive increase in plasma Phe levels concomitant with cardiac dysfunction, whilst p21 deficiency prevented these changes. Phe treatment triggered cellular senescence, along with complex redox and epigenetic changes in vitro and induced an age-mimicking cardiac deterioration in young WT mice in vivo . Pharmacological restoration of Phe catabolism with BH4 reversed the rise in plasma Phe and senescent cardiac alterations in aged WT mice without affecting myocardial NOS activity. Key observations were reproduced in corresponding human samples and collectively they pointed to hepatic Phe catabolic decline with ensuing elevated plasma Phe levels compromising cardiac integrity. Conclusions: Our findings established a pathogenic role for increased Phe levels in cardiac aging, highlighting modulation of Phe catabolism as a potential therapeutic target for age-associated cardiac impairment.

scholarly journals Dysregulated Phenylalanine Catabolism Plays a Key Role in the Trajectory of Cardiac Aging

Circulation ◽  
2021 ◽  
Author(s):  
Gabor Czibik ◽  
Zaineb Mezdari ◽  
Dogus Murat Altintas ◽  
Juliette Bréhat ◽  
Maria Pini ◽  
...  
Keyword(s):  
Cellular Senescence ◽  
Cardiac Dysfunction ◽  
Phenylalanine Hydroxylase ◽  
Interstitial Fibrosis ◽  
Systolic Dysfunction ◽  
Elevated Plasma ◽  
Cardiac Aging ◽  
Age Related ◽  
The Impact

Background: Aging myocardium undergoes progressive cardiac hypertrophy and interstitial fibrosis with diastolic and systolic dysfunction. Recent metabolomics studies shed light on amino acids in aging. The present study aimed to dissect how aging leads to elevated plasma levels of the essential amino acid phenylalanine (Phe) and how it may promote age-related cardiac dysfunction. Methods: We studied cardiac structure and function, together with Phe catabolism in wild-type (WT) and p21 -/- mice (male; 2 to 24 months), the latter known to be protected from cellular senescence. To explore Phe's effects on cellular senescence and ectopic Phe catabolism we treated cardiomyocytes (primary adult rat or human AC-16) with Phe. To establish a role for Phe in driving cardiac aging, WT male mice were treated twice a day with Phe (200 mg/kg) for a month. We also treated aged WT mice with tetrahydrobiopterin (BH4; 10 mg/kg), the essential cofactor for the Phe-degrading enzyme phenylalanine hydroxylase (PAH), or restricted dietary Phe intake. The impact of senescence on hepatic Phe catabolism was explored in vitro in AML12 hepatocytes treated with Nutlin3a (a p53 activator), with or without p21-targeting siRNA or BH4, with quantification of PAH and tyrosine levels. Results: Natural aging is associated with a progressive increase in plasma Phe levels concomitant with cardiac dysfunction, whilst p21 deletion delayed these changes. Phe treatment induced premature cardiac deterioration in young WT mice, strikingly akin to that occurring with aging, whilst triggering cellular senescence, redox and epigenetic changes. Pharmacological restoration of Phe catabolism with BH4 administration or dietary Phe restriction abrogated the rise in plasma Phe and reversed cardiac senescent alterations in aged WT mice. Observations from aged mice and human samples implicated age-related decline in hepatic Phe catabolism as a key driver of elevated plasma Phe levels and showed increased myocardial PAH-mediated Phe catabolism, a novel signature of cardiac aging. Conclusions: Our findings establish a pathogenic role for increased Phe levels in cardiac aging, linking plasma Phe levels to cardiac senescence via dysregulated Phe catabolism along a hepatic-cardiac axis. They highlight Phe/PAH modulation as a potential therapeutic strategy for age-associated cardiac impairment.

scholarly journals Angptl2 is a Marker of Cellular Senescence: The Physiological and Pathophysiological Impact of Angptl2-Related Senescence

2021 ◽  
Vol 22 (22) ◽  
pp. 12232
Author(s):  
Nathalie Thorin-Trescases ◽  
Pauline Labbé ◽  
Pauline Mury ◽  
Mélanie Lambert ◽  
Eric Thorin
Keyword(s):  
Cell Fate ◽  
Cellular Senescence ◽  
Cellular Response ◽  
Inflammatory Diseases ◽  
Age Related ◽  
A Cell ◽  
Future Work ◽  
The Impact

Cellular senescence is a cell fate primarily induced by DNA damage, characterized by irreversible growth arrest in an attempt to stop the damage. Senescence is a cellular response to a stressor and is observed with aging, but also during wound healing and in embryogenic developmental processes. Senescent cells are metabolically active and secrete a multitude of molecules gathered in the senescence-associated secretory phenotype (SASP). The SASP includes inflammatory cytokines, chemokines, growth factors and metalloproteinases, with autocrine and paracrine activities. Among hundreds of molecules, angiopoietin-like 2 (angptl2) is an interesting, although understudied, SASP member identified in various types of senescent cells. Angptl2 is a circulatory protein, and plasma angptl2 levels increase with age and with various chronic inflammatory diseases such as cancer, atherosclerosis, diabetes, heart failure and a multitude of age-related diseases. In this review, we will examine in which context angptl2 was identified as a SASP factor, describe the experimental evidence showing that angptl2 is a marker of senescence in vitro and in vivo, and discuss the impact of angptl2-related senescence in both physiological and pathological conditions. Future work is needed to demonstrate whether the senescence marker angptl2 is a potential clinical biomarker of age-related diseases.

scholarly journals Comparative Meta-Analysis of Transcriptomics Data during Cellular Senescence andIn VivoTissue Ageing

2015 ◽  
Vol 2015 ◽  
pp. 1-17 ◽  
Author(s):  
Konstantinos Voutetakis ◽  
Aristotelis Chatziioannou ◽  
Efstathios S. Gonos ◽  
Ioannis P. Trougakos
Keyword(s):  
Oxidative Phosphorylation ◽  
Actin Cytoskeleton ◽  
Focal Adhesion ◽  
Cellular Senescence ◽  
Meta Analysis ◽  
Metabolism Regulation ◽  
Age Related ◽  
Mapk Signalling ◽  
Transcriptomics Data

Several studies have employed DNA microarrays to identify gene expression signatures that mark human ageing; yet the features underlying this complicated phenomenon remain elusive. We thus conducted a bioinformatics meta-analysis on transcriptomics data from human cell- and biopsy-based microarrays experiments studying cellular senescence orin vivotissue ageing, respectively. We report that coregulated genes in the postmitotic muscle and nervous tissues are classified into pathways involved in cancer, focal adhesion, actin cytoskeleton, MAPK signalling, and metabolism regulation. Genes that are differentially regulated during cellular senescence refer to pathways involved in neurodegeneration, focal adhesion, actin cytoskeleton, proteasome, cell cycle, DNA replication, and oxidative phosphorylation. Finally, we revealed genes and pathways (referring to cancer, Huntington’s disease, MAPK signalling, focal adhesion, actin cytoskeleton, oxidative phosphorylation, and metabolic signalling) that are coregulated during cellular senescence andin vivotissue ageing. The molecular commonalities between cellular senescence and tissue ageing are also highlighted by the fact that pathways that were overrepresented exclusively in the biopsy- or cell-based datasets are modules either of the same reference pathway (e.g., metabolism) or of closely interrelated pathways (e.g., thyroid cancer and melanoma). Our reported meta-analysis has revealed novel age-related genes, setting thus the basis for more detailed future functional studies.

scholarly journals Calcium channel ITPR2 and mitochondria–ER contacts promote cellular senescence and aging

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Dorian V. Ziegler ◽  
David Vindrieux ◽  
Delphine Goehrig ◽  
Sara Jaber ◽  
Guillaume Collin ◽  
...  
Keyword(s):  
Cellular Senescence ◽  
Calcium Release ◽  
Liver Steatosis ◽  
Metabolic Stress ◽  
Calcium Release Channel ◽  
Release Channel ◽  
Age Related ◽  
Trisphosphate Receptor

AbstractCellular senescence is induced by stresses and results in a stable proliferation arrest accompanied by a pro-inflammatory secretome. Senescent cells accumulate during aging, promoting various age-related pathologies and limiting lifespan. The endoplasmic reticulum (ER) inositol 1,4,5-trisphosphate receptor, type 2 (ITPR2) calcium-release channel and calcium fluxes from the ER to the mitochondria are drivers of senescence in human cells. Here we show that Itpr2 knockout (KO) mice display improved aging such as increased lifespan, a better response to metabolic stress, less immunosenescence, as well as less liver steatosis and fibrosis. Cellular senescence, which is known to promote these alterations, is decreased in Itpr2 KO mice and Itpr2 KO embryo-derived cells. Interestingly, ablation of ITPR2 in vivo and in vitro decreases the number of contacts between the mitochondria and the ER and their forced contacts induce premature senescence. These findings shed light on the role of contacts and facilitated exchanges between the ER and the mitochondria through ITPR2 in regulating senescence and aging.

Cardiomyopathy in transgenic mice with cardiac-specific overexpression of serum response factor

2001 ◽  
Vol 280 (4) ◽  
pp. H1782-H1792 ◽  
Author(s):  
Xiaomin Zhang ◽  
Gohar Azhar ◽  
Jianyuan Chai ◽  
Pamela Sheridan ◽  
Koichiro Nagano ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Cardiac Muscle ◽  
Serum Response Factor ◽  
Interstitial Fibrosis ◽  
Weight Ratio ◽  
Heart Weight ◽  
Cardiomyocyte Hypertrophy ◽  
Response Factor ◽  
Serum Response

Serum response factor (SRF), a member of the MCM1, agamous, deficiens, SRF (MADS) family of transcriptional activators, has been implicated in the transcriptional control of a number of cardiac muscle genes, including cardiac α-actin, skeletal α-actin, α-myosin heavy chain (α-MHC), and β-MHC. To better understand the in vivo role of SRF in regulating genes responsible for maintenance of cardiac function, we sought to test the hypothesis that increased cardiac-specific SRF expression might be associated with altered cardiac morphology and function. We generated transgenic mice with cardiac-specific overexpression of the human SRF gene. The transgenic mice developed cardiomyopathy and exhibited increased heart weight-to-body weight ratio, increased heart weight, and four-chamber dilation. Histological examination revealed cardiomyocyte hypertrophy, collagen deposition, and interstitial fibrosis. SRF overexpression altered the expression of SRF-regulated genes and resulted in cardiac muscle dysfunction. Our results demonstrate that sustained overexpression of SRF, in the absence of other stimuli, is sufficient to induce cardiac change and suggest that SRF is likely to be one of the downstream effectors of the signaling pathways involved in mediating cardiac hypertrophy.

Abstract 123: Age-Related Endothelial Senescence is Driven by Thrombospondin-1-Activated NADPH Oxidase Nox1

Hypertension ◽  
2015 ◽  
Vol 66 (suppl_1) ◽  
Author(s):  
Daniel N Meijles ◽  
Imad Al Ghouleh ◽  
Sanghamitra Sahoo ◽  
Jefferson H Amaral ◽  
Heather Knupp ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Nadph Oxidase ◽  
Vascular Diseases ◽  
Dependent Manner ◽  
Wild Type ◽  
Molecular Control ◽  
Redox Biology ◽  
Age Related ◽  
P53 Activation

Organismal aging represents an independent risk factor underlying many vascular diseases, including systemic and pulmonary hypertension, and atherosclerosis. While the mechanisms driving aging are largely elusive, a steady persistent increase in tissue oxidative stress has been associated with senescence. Previously we showed TSP1 elicits NADPH oxidase (Nox)-dependent vascular smooth muscle cell oxidative stress. However mechanisms by which TSP1 affects endothelial redox biology are unknown. Here, we tested the hypothesis that TSP1 induces endothelial oxidative stress-linked senescence in aging. Using rapid autopsy disease-free human pulmonary (PA) artery, we identified a significant positive correlation between age, protein levels of TSP1, Nox1 and the cell-cycle repressor p21cip (p<0.05). Age also positively associated with increased Amplex Red-detected PA hydrogen peroxide levels (p<0.05). Moreover, treatment of human PA endothelial cells (HPAEC) with TSP1 (2.2nM; 24h) increased expression (~1.9 fold; p<0.05) and activation of Nox1 (~1.7 fold; p<0.05) compared to control, as assessed by Western blot and SOD-inhibitable cytochrome c reduction. Western blotting and immunofluorescence showed a TSP1-mediated increase in p53 activation, indicative of the DNA damage response. Moreover, TSP1 significantly increased HPAEC senescence in a p53/p21cip/Rb-dependent manner, as assessed by immunofluorescent detection of subcellular localization and senescence-associated β-galactosidase staining. To explore this pathway in vivo, middle-aged (8-10 month) wild-type and TSP1-null mice were utilized. In the TSP1-null, reduced lung senescence, oxidative stress, Nox1 levels and p21cip expression were observed compared to wild-type supporting findings in human samples and cell experiments. Finally, prophylactic treatment with specific Nox1 inhibitor NoxA1ds (10μM) attenuated TSP1-induced HPAEC ROS, p53 activation, p21cip expression and senescence. Taken together, our results provide molecular insight into the functional interplay between TSP1 and Nox1 in the regulation of endothelial senescence, with implications for molecular control of the aging process.

Abstract 321: Combination Dri With At1R Blockade Does Not Confer Additional Benefit to Improvement in Myocardial Tissue Hypertrophy and Fibrosis

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Adam T Whaley-Connell ◽  
Javad Habibi ◽  
Nathan Rehmer ◽  
Sivakumar Ardhanari ◽  
Anand Chockalingham ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Interstitial Fibrosis ◽  
Mammalian Target Of Rapamycin ◽  
Left Ventricular ◽  
Cardiomyocyte Hypertrophy ◽  
Sprague Dawley ◽  
Serum Aldosterone ◽  
Markers Of Oxidative Stress ◽  
Renin Inhibition

Data support the notion that direct renin inhibition and angiotensin type 1 receptor (AT 1 R) blockade improve myocardial hypertrophy and fibrosis. Even with contemporary use of AT 1 R blockade and renin inhibition, the burden of heart failure remains high. Thereby, we sought to determine if combination of direct renin inhibition with AT 1 R blockade in vivo , through greater reductions in systolic blood pressure (SBP) and aldosterone would attenuate left ventricular (LV) hypertrophy and interstitial fibrosis to a greater extent than either intervention alone. We utilized the transgenic Ren2 rat which manifests increased expression of murine renin which, in turn, results in increased tissue RAS activity, aldosterone secretion and elevated SBP. Ren2 rats were treated with renin inhibition (aliskiren), AT 1 R blockade (valsartan), the combination (aliskiren+valsartan), or vehicle for 21 days. Compared to Sprague-Dawley controls, Ren2 rats displayed increased SBP, serum aldosterone levels, LV and cardiomyocyte hypertrophy, interstitial fibrosis and ultrastructural remodeling. These biochemical and functional alterations were accompanied by increases in LV tissue NADPH oxidase subunit Nox2 and 3-nitrotyrosine (3-NT) content along with increases in mammalian target of rapamycin (mTOR) and reductions in protein kinase B phosphorylation. Combination therapy contributed to greater reductions in SBP and serum aldosterone but did not result in greater improvement in metabolic signaling or markers of oxidative stress, fibrosis or hypertrophy beyond either intervention alone. Thereby, our data suggest that the greater impact of combination therapy on reductions in aldosterone does not translate into greater reductions in myocardial fibrosis or hypertrophy in this transgenic model of tissue renin overexpression.

Abstract 250: Acting Instructor

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Huiliang Zhang ◽  
Nathan Alder ◽  
Wang Wang ◽  
Hazel Szeto ◽  
David Marcinek ◽  
...  
Keyword(s):  
Heart Failure ◽  
Diastolic Dysfunction ◽  
Cardiac Dysfunction ◽  
Mitochondrial Permeability Transition ◽  
Adenine Nucleotide ◽  
Proton Leak ◽  
Ph Indicator ◽  
Cardiac Aging ◽  
Age Related

Rational: Aging-associated diseases, including cardiac dysfunction, are increasingly common in the population. However, the mechanisms of physiologic aging in general, and cardiac aging in particular, remain poorly understood. While effective medical interventions are available for some kinds of heart failure, one age-related impairment, diastolic dysfunction in Heart Failure with Preserved Ejection Fraction (HFpEF) is lacking a clinically effective treatment. Methods and Results: Using the pH indicator cpYFP in the model of naturally aging mice and rats, we show direct evidence of increased mitochondrial proton leak in aged heart mitochondria following a pH gradient stress. Furthermore, we identified Adenine Nucleotide Translocator 1 (ANT1) as mediating the increased proton permeability of old cardiomyocytes. Most importantly, acute (2 hours) in vitro treatment with the tetra-peptide drug SS-31 (elamipretide) reverses age-related excess proton entry, decreases the mitochondrial flash activity and mitochondrial permeability transition pore (mPTP) opening and rejuvenates mitochondrial function. Moreover, we show that SS-31 benefits the old mitochondria by direct association with ANT1 and stabilization of the mitochondrial ATP synthasome, leading to substantial reversal of diastolic dysfunction. Conclusion: Our results uncover excessive mitochondrial proton leak as a novel mechanism of age-related cardiac dysfunction and elucidate how SS-31 is able to reverse this clinically important complication of cardiac aging.

scholarly journals Intracellular Dyssynchrony of Diastolic Cytosolic [Ca 2+ ] Decay in Ventricular Cardiomyocytes in Cardiac Remodeling and Human Heart Failure

2013 ◽  
Vol 113 (5) ◽  
pp. 527-538 ◽  
Author(s):  
Felix Hohendanner ◽  
Senka Ljubojević ◽  
Niall MacQuaide ◽  
Michael Sacherer ◽  
Simon Sedej ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Remodeling ◽  
Human Heart ◽  
Cyclopiazonic Acid ◽  
Cardiomyocyte Hypertrophy ◽  
Human Heart Failure ◽  
Mitochondrial Density ◽  
Human Cardiomyocytes ◽  
End Stage ◽  
The Impact

Rationale : Synchronized release of Ca 2+ into the cytosol during each cardiac cycle determines cardiomyocyte contraction. Objective: We investigated synchrony of cytosolic [Ca 2+ ] decay during diastole and the impact of cardiac remodeling. Methods and Results: Local cytosolic [Ca 2+ ] transients (1-µm intervals) were recorded in murine, porcine, and human ventricular single cardiomyocytes. We identified intracellular regions of slow (slowCaR) and fast (fastCaR) [Ca 2+ ] decay based on the local time constants of decay (TAU local ). The SD of TAU local as a measure of dyssynchrony was not related to the amplitude or the timing of local Ca 2+ release. Stimulation of sarcoplasmic reticulum Ca 2+ ATPase with forskolin or istaroxime accelerated and its inhibition with cyclopiazonic acid slowed TAU local significantly more in slowCaR, thus altering the relationship between SD of TAU local and global [Ca 2+ ] decay (TAU global ). Na + /Ca 2+ exchanger inhibitor SEA0400 prolonged TAU local similarly in slowCaR and fastCaR. FastCaR were associated with increased mitochondrial density and were more sensitive to the mitochondrial Ca 2+ uniporter blocker Ru360. Variation in TAU local was higher in pig and human cardiomyocytes and higher with increased stimulation frequency (2 Hz). TAU local correlated with local sarcomere relengthening. In mice with myocardial hypertrophy after transverse aortic constriction, in pigs with chronic myocardial ischemia, and in end-stage human heart failure, variation in TAU local was increased and related to cardiomyocyte hypertrophy and increased mitochondrial density. Conclusions: In cardiomyocytes, cytosolic [Ca 2+ ] decay is regulated locally and related to local sarcomere relengthening. Dyssynchronous intracellular [Ca 2+ ] decay in cardiac remodeling and end-stage heart failure suggests a novel mechanism of cellular contractile dysfunction.

scholarly journals MR imaging of model drug distribution in simulated vitreous

2015 ◽  
Vol 1 (1) ◽  
pp. 236-239 ◽  
Author(s):  
Sandra Stein ◽  
Christian Simroth-Loch ◽  
Sönke Langner ◽  
Stefan Hadlich ◽  
Oliver Stachs ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Ex Vivo ◽  
Drug Distribution ◽  
Injection Technique ◽  
Innovative Therapy ◽  
Age Related ◽  
The Impact

AbstractThe in vitro and in vivo characterization of intravitreal injections plays an important role in developing innovative therapy approaches. Using the established vitreous model (VM) and eye movement system (EyeMoS) the distribution of contrast agents with different molecular weight was studied in vitro. The impact of the simulated age-related vitreal liquefaction (VL) on drug distribution in VM was examined either with injection through the gel phase or through the liquid phase. For comparison the distribution was studied ex vivo in the porcine vitreous. The studies were performed in a magnetic resonance (MR) scanner. As expected, with increasing molecular weight the diffusion velocity and the visual distribution of the injected substances decreased. Similar drug distribution was observed in VM and in porcine eye. VL causes enhanced convective flow and faster distribution in VM. Confirming the importance of the injection technique in progress of VL, injection through gelatinous phase caused faster distribution into peripheral regions of the VM than following injection through liquefied phase. VM and MR scanner in combination present a new approach for the in vitro characterization of drug release and distribution of intravitreal dosage forms.

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