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.

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.

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 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 Reduction of Elevated Proton Leak Rejuvenates Mitochondria in the Aged Cardiomyocyte

2020 ◽  
Vol 4 (Supplement_1) ◽  
pp. 524-524
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

Abstract 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 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.

scholarly journals Neuroinflammation in Aged Brain: Impact of the Oral Administration of Ellagic Acid Microdispersion

2020 ◽  
Vol 21 (10) ◽  
pp. 3631 ◽  
Author(s):  
Raffaella Boggia ◽  
Federica Turrini ◽  
Alessandra Roggeri ◽  
Guendalina Olivero ◽  
Francesca Cisani ◽  
...  
Keyword(s):  
Oral Administration ◽  
Ellagic Acid ◽  
Ex Vivo ◽  
Behavioral Skills ◽  
Aged Mice ◽  
Age Related ◽  
The Central Nervous System ◽  
The Impact ◽  
Old Mice

The immune system and the central nervous system message each other to preserving central homeostasis. Both systems undergo changes during aging that determine central age-related defects. Ellagic acid (EA) is a natural product which is beneficial in both peripheral and central diseases, including aging. We analyzed the impact of the oral administration of a new oral ellagic acid micro-dispersion (EAm), that largely increased the EA solubility, in young and old mice. Oral EAm did not modify animal weight and behavioral skills in young and old mice, but significantly recovered changes in “ex-vivo, in vitro” parameters in old animals. Cortical noradrenaline exocytosis decreased in aged mice. EAm administration did not modify noradrenaline overflow in young animals, but recovered it in old mice. Furthermore, GFAP staining was increased in the cortex of aged mice, while IBA-1 and CD45 immunopositivities were unchanged when compared to young ones. EAm treatment significantly reduced CD45 signal in both young and old cortical lysates; it diminished GFAP immunopositivity in young mice, but failed to affect IBA-1 expression in both young and old animals. Finally, EAm treatment significantly reduced IL1beta expression in old mice. These results suggest that EAm is beneficial to aging and represents a nutraceutical ingredient for elders.

P2255Senescence associated secretory phenotype exacerbates overload pressure-cardiac hypertrophy

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
D B Nugroho ◽  
K Ikeda ◽  
A Haryono ◽  
P Rinastiti ◽  
A J Barinda ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Conditioned Medium ◽  
Cardiac Dysfunction ◽  
Cardiac Tissue ◽  
Histological Analysis ◽  
Tissue Homeostasis ◽  
Heart Weight ◽  
Age Related ◽  
Secretory Phenotype

Abstract Background Advanced age is a significant risk factor for cardiovascular diseases such as hypertension and cardiac hypertrophy. The vascular system forms an essential component of cardiac tissue, to provide routes for circulation and transportation of nutrients and oxygen throughout the cardiac muscle. In addition to its function in vascular biology such as vasodilation and neovessel formation, endothelial cell (EC) also provides many secreted angiocrine factors that are crucially involved in maintaining tissue homeostasis. Ageing induces cellular senescence in various cells including EC. Senescent cells produce senescence-messaging secretomes that have deleterious effects on the tissue microenvironment, referred to as the senescence-associated secretory phenotype (SASP). Because of the crucial roles of EC in tissue homeostasis, EC senescence is presumed to play significant roles in age-related cardiac dysfunction, however, whether and the mechanism by which EC senescence affects age-related cardiac dysfunction remains to be elucidated. Purpose We aimed to investigate the role of senescent ECs in cardiac hypertrophy and heart function. Methods To investigate a contribution of senescent EC in age-related cardiac tissue dysfunction in vivo, we generated EC-specific progeroid mice that overexpress the dominant negative form of telomeric repeat-binding factor 2 (TRF2), which play a central role in the protection of chromosome ends, under the control of the vascular endothelial cadherin promoter (VEcad-TRF2DN-Tg). To induce pathological cardiac remodeling, Transverse Aortic Constriction (TAC) was performed in mice at the age of 10–12 weeks old. Cardiac function was assessed using fractional shortening percentage and ejection fraction measured with echocardiography every week until sacrifice day. Mice were sacrificed 4 weeks after TAC, heart tissue was collected for histological analysis, cardiac morphometry analysis, gene expression and protein expression analysis. In vitro, H9C2 rat cardiomyoblast cells were incubated with conditioned medium derived from control or senescent EC in the presence or absence of angiotensin II to induce cardiac hypertrophy. Results The serial echocardiographic analysis after TAC revealed the exacerbated LV dysfunction in VEcad-TRF2DN-Tg compared to that in wild-type mice. Morphometric and histological analysis 4 weeks after TAC showed increased heart weight and aggravated cardiac fibrosis in VEcad-TRF2DN-Tg mice. In vitro studies demonstrated that conditioned medium derived from senescent ECs enhanced cardiomyocyte hypertrophy in H9C2 cells. Of note, we found that treatment with Y2762, a Rho Kinase inhibitor, canceled the exacerbated cardiac hypertrophy caused by endothelial SASP. Conclusion These findings demonstrate for the first time that senescent ECs play causative roles in age-related cardiac disorders through the SASP, potentially by activating Rho-ROCK pathway in cardiomyocytes.

Mice with Megakaryocyte-Specific Deletion of TGF-β1 Are Partially Protected From Developing Cardiac Fibrosis and Systolic Dysfunction in a Pressure Overload Model

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 362-362
Author(s):  
Alexander Meyer ◽  
Wei Wang ◽  
Jay L. Degen ◽  
Barry S. Coller ◽  
Jasimuddin Ahamed
Keyword(s):  
Shear Force ◽  
Cardiac Fibrosis ◽  
Interstitial Fibrosis ◽  
Systolic Dysfunction ◽  
Heart Weight ◽  
Tgf Β1 ◽  
Specific Deletion ◽  
Severe Fibrosis

Abstract Abstract 362 Circulating platelets contain a high concentration of the multifunctional cytokine transforming growth factor-β1 (TGF-β1) in their α-granules and release it as an inactive (latent) complex upon platelet adhesion and/or activation. We recently demonstrated that shear force can activate latent TGF-β1 in vitro, and this mechanism may contribute to the activation of TGF-β1 that we observed in vivo in the carotid arteries following injury and thrombus formation. TGF-β1 is reported to be involved in the development of cardiac fibrosis in both humans and mouse models, but the cellular source(s) of TGF-β1 and its activation mechanism in vivo have not been clearly established. To test the hypothesis that platelet TGF-β1 contributes to cardiac fibrosis, we performed comparative studies of WT mice and gene-targeted animals with a megakaryocyte-specific deletion of TGF-β1 [PF4-Cre/Tgfb1flox (Tgfb1flox)] using the transverse aortic constriction (TAC) model in male C57Bl/6 mice. Both groups also underwent sham surgery as controls. We obtained blood by percutaneous puncture of the LV under ultrasound guidance and plasma samples were prepared by immediate centrifugation at 12,000 g for 5 min. This technique consistently results in plasma TGF-β1 levels in the range of ∼1.0 ng/ml, which are below those previously reported by most investigators. Tgfb1flox mice had 45% lower levels of plasma total TGF-β1 than WT animals, with a median total TGF-β1 level in WT of 1.37 ng/ml (IQR, interquartile range, 1.2–1.6; n=45) compared to 0.76 ng/ml (IQR 0.6–0.9; n=25)] in Tgfb1flox mice (p<0.001). Heart weight/body weight ratios were 42% higher in TAC- (n=15) than in sham- (n=16) operated WT mice (p<0.001) after 4 weeks, but only 11% higher in TAC- (n=13) than sham- (n=12) operated Tgfb1flox mice (p=0.02). The heart weight/body weight ratios correlated with total TGF-β1 levels in WT mice undergoing both sham and TAC surgery (r=0.66; p<0.001), but not in Tgfb1flox mice. Cardiac fibrosis was scored 4 weeks after surgery by an expert veterinary pathologist as 0 for no fibrosis, and 1+, 2+, or 3+ for mild, moderate, and severe fibrosis, respectively. 96% (22/23) of WT mice developed interstitial fibrosis after TAC, with 65% (15/23) developing mild and 30% (7/23) developing moderate (6/23) or severe (1/23) fibrosis. In contrast, only 54% (7/13) of Tgfb1flox mice developed interstitial fibrosis, with 31% (4/13) developing mild and 15% (2/13) developing moderate fibrosis; none developed severe fibrosis (p<0.01). The Tgfb1flox mice also had significantly less perivascular fibrosis than did the WT mice, although the differences were less evident (p=0.03). Cardiac function measured by echocardiography one week after TAC surgery demonstrated that Tgfb1flox mice had better systolic function than WT mice (Table).Table:Cardiac function measurements one week after TAC surgery.WTTgfb1flox†pEF [%]41 [37–48; n=11]56 [48–65; n=11]0.03SV [μl]20 [18–21; n=11]28 [24–33; n=11]0.003FS (%)27 [23–30; n=14]32 [28–37; n=13]0.05EF: ejection fraction; SV: stroke volume; FS: fractional shortening. Data are reported as median [IQR] †Wilcoxon Rank-Sum test. Presurgery values for EF, SV, and FS were similar in WT and Tgfb1flox mice We conclude that platelet TGF-β1 contributes to the development of cardiac hypertrophy, fibrosis, and systolic dysfunction induced by a high shear, TAC model. These data have important implications for understanding TGF-β1 biology and assessing the role of TGF-β1 in murine models of human diseases. Since shear can dramatically activate TGF-β1 in vitro, it is possible that increased shear force in the TAC mice generates active TGF-β1, which may contribute to the development of cardiac hypertrophy, fibrosis, and systolic dysfunction. Disclosures: No relevant conflicts of interest to declare.

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.

scholarly journals Group IVA Cytosolic Phospholipase A2Regulates the G2-to-M Transition by Modulating the Activity of Tumor Suppressor SIRT2

2015 ◽  
Vol 35 (21) ◽  
pp. 3768-3784 ◽  
Author(s):  
Said Movahedi Naini ◽  
Alice M. Sheridan ◽  
Thomas Force ◽  
Jagesh V. Shah ◽  
Joseph V. Bonventre
Keyword(s):  
Tumor Suppressor ◽  
Cyclin A ◽  
Inhibitory Effect ◽  
Mitotic Entry ◽  
Cytosolic Phospholipase ◽  
Age Related ◽  
Group Iva ◽  
The Impact

The G2-to-M transition (or prophase) checkpoint of the cell cycle is a critical regulator of mitotic entry. SIRT2, a tumor suppressor gene, contributes to the control of this checkpoint by blocking mitotic entry under cellular stress. However, the mechanism underlying both SIRT2 activation and regulation of the G2-to-M transition remains largely unknown. Here, we report the formation of a multiprotein complex at the G2-to-M transitionin vitroandin vivo. Group IVA cytosolic phospholipase A2(cPLA2α) acts as a bridge in this complex to promote binding of SIRT2 to cyclin A-Cdk2. Cyclin A-Cdk2 then phosphorylates SIRT2 at Ser331. This phosphorylation reduces SIRT2 catalytic activity and its binding affinity to centrosomes and mitotic spindles, promoting G2-to-M transition. We show that the inhibitory effect of cPLA2α on SIRT2 activity impacts various cellular processes, including cellular levels of histone H4 acetylated at K16 (Ac-H4K16) and Ac-α-tubulin. This regulatory effect of cPLA2α on SIRT2 defines a novel function of cPLA2α independent of its phospholipase activity and may have implications for the impact of SIRT2-related effects on tumorigenesis and age-related diseases.

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