Abstract 867: The Longevity Factor Sirt1 Exacerbates LV Dysfunction and Energy Depletion in Response to Pressure Overload

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Ralph Alcendor ◽  
Chull Hong ◽  
Peiyong Zhai ◽  
Shumin Gao ◽  
Junichi Sadoshima
Keyword(s):  
Oxidative Stress ◽  
Stress Resistance ◽  
Diastolic Pressure ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Class Iii ◽  
Lung Weight ◽  
Energy Depletion ◽  
Lv Dysfunction ◽  
And Oxidative Stress

Sirt1, a class III histone deacetylase, extends the lifespan of many organisms. Longevity mechanisms usually confer stress resistance to organisms, and accumulation of stress resistance leads to lifespan extension. We have shown previously that Sirt1 is upregulated by stress up to 10 fold in the heart, and heart specific overexpression (up to 7.5 fold) of Sirt1 in mice not only suppresses histological/biochemical markers of aging, but also induces resistance to oxidative stress in the heart. We examined whether Sirt1 is protective against another pathologically relevant stimulus, namely pressure overload. Cardiac specific Sirt1 transgenic mice (Tg-Sirt1) from line #40, the line which has been shown to be protected against aging and oxidative stress, were subjected to transverse aortic constriction (TAC). Unexpectedly, at 10 days, the left ventricular (LV) ejection fraction (EF) in Tg-Sirt1 was significantly reduced (46 vs 71%, p<0.01), the LV end diastolic dimension was significantly increased (4.1 vs 3.4 mm, p<0.05), and the pressure gradient was reduced (92 vs 57 mmHg, p<0.05), possibly due to reduced LV contractility, in Tg-Sirt1 compared with non-transgenic (NTg) controls. At 4 weeks, LV weight/body weight (BW) (6.4 vs 4.7, p<0.05) and lung weight/BW (18.8 vs 7.0, p<0.05) were significantly increased in Tg-Sirt1, LV +dP/dt was significantly reduced (4617 vs 7513, p<0.05), and the LV end diastolic pressure was significantly elevated (13.6 vs 1.4 mmHg, p<0.05) in Tg-Sirt1 compared with NTg. These results suggest that Tg-Sirt1 mice develop more severe LV dysfunction than NTg in response to TAC. Tg-Sirt1 mice exhibited significantly less apoptosis (−50%, p<0.05) than NTg however, despite the development of LV dysfunction, suggesting that the LV dysfunction may be caused by apoptosis-independent mechanisms. The myocardial ATP content in Tg-Sirt1 was significantly less (−41%, p<0.05) than that in NTg after TAC. These results suggest that the cardioprotective effect of Sirt1 depends on the type of stress: although modest expression of Sirt1 confers resistance to aging and oxidative stress, it exacerbates heart failure in response to TAC through apoptosis-independent mechanisms possibly involving energy depletion.

Abstract 13469: Drp1 Accumulates in Mitochondria and Plays a Protective Role in the Heart in Response to Pressure Overload

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Akihiro Shirakabe ◽  
Yoshiyuki Ikeda ◽  
Peiyong Zai ◽  
Junichi Sadoshima
Keyword(s):  
Diastolic Pressure ◽  
Pressure Overload ◽  
Protective Role ◽  
Left Ventricular ◽  
Multiple Time ◽  
Lung Weight ◽  
Knock Out ◽  
Multiple Time Points ◽  
Increased Activity ◽  
Adaptive Role

Dynamin-related protein 1 (Drp1) plays an essential role in maintaining the quality control of mitochondria through mitochondrial (Mt) fission and mitophagy. We investigated how Mt function, autophagy and Drp1 are regulated in the heart during pressure overload (PO) and whether endogenous Drp1 plays an important role in regulating cardiac function. Mice were subjected to transverse aortic constriction (TAC) at multiple time points between 6 hours and 30 days. Left ventricular (LV) weight/tibial length (LVW/TL) was significantly elevated at Day 7 (TAC vs sham; 5.92 ± 0.27 vs 4.22 ± 0.12, p<0.05). Ejection fraction (EF) was maintained at Day 7, but gradually decreased thereafter (at 30 days; 65±9 vs 83±9 %, p<0.05). LC3-II was decreased (-45.7%, p<0.05) while p62 accumulated (1.17 fold, p<0.05) significantly at Day 7. Both Mt ATP content (-65.6%, p<0.05) and production (-90.3%, p<0.05) were reduced significantly at Days 7 and 14, respectively, and thereafter. Mt mass, evaluated by electron microscopy, was also reduced (-19.9%, p<0.05) at Day 7. Drp1 accumulated in mitochondria at Day 7, and S616 phosphorylation of Drp1, associated with increased activity, was increased at Day 7. Thus, PO suppresses autophagy and induces Mt dysfunction by Day 7, at which time Drp1 accumulates in mitochondria and Mt mass is decreased. To examine the functional significance of endogenous Drp1 during PO, cardiac-specific heterozygous Drp1 knock out (Drp-hetCKO) mice were subjected to TAC. At Day 7, decreases in EF (61± 2 vs 84 ± 7%, p<0.05) and increases in LVW/TL (7.22 ± 0.26 vs 5.86 ± 0.65, p<0.05) and lung weight/TL (12.01 ± 1.10 vs 6.31 ± 1.19, p<0.05) were exacerbated in Drp-hetCKO compared to in control mice. LV end diastolic pressure was significantly higher (22.0 ± 2.8 vs 5.7 ± 2.9 mmHg, p<0.05) and myocardial fibrosis (14.1 ± 2.5 vs 6.2 ± 4.3 %, p<0.05) was greater in Drp-hetCKO than in control mice. Mt mass was also significantly greater in Drp-hetCKO than in control mice (relative Mt mass, 1.21 ± 0.46 vs 1.00 ± 0.02, p<0.05). These results suggest that PO inhibits autophagy and induces mitochondrial dysfunction by Day7, which coincides with Mt accumulation of Drp1. Drp1 plays an adaptive role in this condition, mediating decreases in Mt mass and protecting the heart from dysfunction.

Apoptosis in the left ventricle of chronic volume overload causes endocardial endothelial dysfunction in rats

2002 ◽  
Vol 282 (4) ◽  
pp. H1197-H1205 ◽  
Author(s):  
Michael J. Cox ◽  
Harpreet S. Sood ◽  
Matthew J. Hunt ◽  
Derrick Chandler ◽  
Jeffrey R. Henegar ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Blot Analysis ◽  
Diastolic Pressure ◽  
Volume Overload ◽  
Left Ventricular ◽  
Tissue Inhibitor Of Metalloproteinase ◽  
Heart Weight ◽  
Sprague Dawley ◽  
Lung Weight ◽  
Cardiac Relaxation

The hypothesis is that chronic increases in left ventricular (LV) load induce oxidative stress and latent matrix metalloproteinase (MMP) is activated, allowing the heart to dilate in the absence of endothelial nitric oxide (NO) and thereby reduce filling pressure. To create volume overload, an arteriovenous (A-V) fistula was placed in male Sprague-Dawley rats. To decrease oxidative stress and apoptosis, 0.08 mg/ml nicotinamide (Nic) was administered in drinking water 2 days before surgery. The rats were divided into the following groups: 1) A-V fistula, 2) A-V fistula + Nic, 3) sham operated, 4) sham + Nic, and 5) control (unoperated); n = 6 rats/group. After 4 wk, hemodynamic parameters were measured in anesthetized rats. The heart was removed and weighed, and LV tissue homogeneates were prepared. A-V fistula caused an increase in heart weight, lung weight, and end-diastolic pressure compared with the sham group. The levels of malondialdehyde (MDA; a marker of oxidative stress) was 6.60 ± 0.23 ng/mg protein and NO was 6.87 ± 1.21 nmol/l in the LV of A-V fistula rats by spectrophometry. Nic treatment increased NO to 13.88 ± 2.5 nmol/l and decreased MDA to 3.54 ± 0.34 ng/mg protein ( P= 0.005). Zymographic levels of MMP-2 were increased, as were protein levels of nitrotyrosine and collagen fragments by Western blot analysis. The inhibition of oxidative stress by Nic decreased nitrotyrosine content and MMP activity. The levels of tissue inhibitor of metalloproteinase-4 mRNA were decreased in A-V fistula rats and increased in A-V fistula rats treated with Nic by Northern blot analysis. TdT-mediated dUTP nick-end labeling-positive cells were increased in A-V fistula rats and decreased in fistula rats treated with Nic. Acetylcholine and nitroprusside responses in cardiac rings prepared from the above groups of rats suggest impaired endothelial-dependent cardiac relaxation. Treatment with Nic improves cardiac relaxation. The results suggest that an increase in the oxidative stress and generation of nitrotyrosine are, in part, responsible for the activation of metalloproteinase and decreased endocardial endothelial function in chronic LV volume overload.

scholarly journals Alleviation of Inflammation and Oxidative Stress in Pressure Overload-Induced Cardiac Remodeling and Heart Failure via IL-6/STAT3 Inhibition by Raloxifene

2021 ◽  
Vol 2021 ◽  
pp. 1-15
Author(s):  
Shengqi Huo ◽  
Wei Shi ◽  
Haiyan Ma ◽  
Dan Yan ◽  
Pengcheng Luo ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Protein Expression ◽  
Cardiac Remodeling ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Stat3 Signaling ◽  
H9c2 Myoblasts ◽  
And Oxidative Stress ◽  
Stat3 Inhibition

Background. Inflammation and oxidative stress are involved in the initiation and progress of heart failure (HF). However, the role of the IL6/STAT3 pathway in the pressure overload-induced HF remains controversial. Methods and Results. Transverse aortic constriction (TAC) was used to induce pressure overload-HF in C57BL/6J mice. 18 mice were randomized into three groups (Sham, TAC, and TAC+raloxifene, n = 6 , respectively). Echocardiographic and histological results showed that cardiac hypertrophy, fibrosis, and left ventricular dysfunction were manifested in mice after TAC treatment of eight weeks, with aggravation of macrophage infiltration and interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) expression in the myocardium. TAC (four and eight weeks) elevated the phosphorylation of signal transducer and activator of transcription 3 (p-STAT3) and prohibitin2 (PHB2) protein expression. Importantly, IL-6/gp130/STAT3 inhibition by raloxifene alleviated TAC-induced myocardial inflammation, cardiac remodeling, and dysfunction. In vitro, we demonstrated cellular hypertrophy with STAT3 activation and oxidative stress exacerbation could be elicited by IL-6 (25 ng/mL, 48 h) in H9c2 myoblasts. Sustained IL-6 stimulation increased intracellular reactive oxygen species, repressed mitochondrial membrane potential (MMP), decreased intracellular content of ATP, and led to decreased SOD activity, an increase in iNOS protein expression, and increased protein expression of Pink1, Parkin, and Bnip3 involving in mitophagy, all of which were reversed by raloxifene. Conclusion. Inflammation and IL-6/STAT3 signaling were activated in TAC-induced HF in mice, while sustained IL-6 incubation elicited oxidative stress and mitophagy-related protein increase in H9c2 myoblasts, all of which were inhibited by raloxifene. These indicated IL-6/STAT3 signaling might be involved in the pathogenesis of myocardial hypertrophy and HF.

Abstract 168: Drp1 Accumulates in Mitochondria and Plays a Protective Role in the Heart in Response to Pressure Overload

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Akihiro Shirakabe ◽  
Yoshiyuki Ikeda ◽  
Toshiro Saito ◽  
Peiyong Zhai ◽  
Junichi Sadoshima
Keyword(s):  
Diastolic Pressure ◽  
Pressure Overload ◽  
Protective Role ◽  
Left Ventricular ◽  
Multiple Time ◽  
Lung Weight ◽  
Knock Out ◽  
Multiple Time Points ◽  
Increased Activity ◽  
Adaptive Role

Dynamin-related protein 1 (Drp1) plays an essential role in maintaining the quality control of mitochondria through mitochondrial (Mt) fission and mitophagy. We investigated how Mt function, autophagy and Drp1 are regulated in the heart during pressure overload (PO) and whether endogenous Drp1 plays an important role in regulating cardiac function. Mice were subjected to transverse aortic constriction (TAC) at multiple time points between 6 hours and 30 days. Left ventricular (LV) weight/tibial length (LVW/TL) was significantly elevated at Day 5 (TAC vs Baseline; 6.21 ± 0.28 vs 4.59 ± 0.36, p<0.05). Ejection fraction (EF) was maintained at Day 5 (79±5 vs 82±7%), but gradually decreased thereafter (30 days; 51±12%, p<0.05). LC3-II was decreased (-40.0%, p<0.05) while p62 accumulated (1.84 fold, p<0.05) significantly at Day 5. Both Mt ATP content (-65.6%, p<0.05) and production (-90.3%, p<0.05) were reduced significantly at Days 7 and 14, respectively, and thereafter. Mt mass, evaluated by electron microscopy, was also reduced (-19.9%, p<0.05) at Day 7. Drp1 accumulated in mitochondria at Day 7, and S616 phosphorylation of Drp1, associated with increased activity, was increased at Day 7. Thus, PO suppresses autophagy and induces Mt dysfunction by Day 7, at which time Drp1 accumulates in mitochondria and Mt mass is decreased. To examine the functional significance of endogenous Drp1 during PO, cardiac-specific heterozygous Drp1 knock out (Drp-hetCKO) mice were subjected to TAC. At Day 7, decreases in EF (57± 11 vs 80 ± 7%, p<0.05) and increases in LVW/TL (7.22 ± 0.26 vs 5.86 ± 0.65, p<0.05) and lung weight/TL (13.03 ± 1.09 vs 7.00 ± 1.31, p<0.05) were exacerbated in Drp-hetCKO compared to in control mice. LV end diastolic pressure was significantly higher (20.0 ± 5.7 vs 7.4 ± 3.1 mmHg, p<0.05) and myocardial fibrosis (14.1 ± 2.5 vs 6.2 ± 4.3 %, p<0.05) was greater, and Mt mass was also significantly greater in Drp-hetCKO than in control mice (relative Mt mass, 1.21 ± 0.46 vs 1.00 ± 0.02, p<0.05). These results suggest that PO inhibits autophagy and induces mitochondrial dysfunction by Day7, which coincides with Mt accumulation of Drp1. Drp1 plays an adaptive role in this condition, mediating decreases in Mt mass and protecting the heart from dysfunction.

scholarly journals Maternal Fructose Intake Exacerbates Cardiac Remodeling in Offspring with Ventricular Pressure Overload

Nutrients ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 3267
Author(s):  
Steve Leu ◽  
Kay L. H. Wu ◽  
Wei-Chia Lee ◽  
You-Lin Tain ◽  
Julie Y. H. Chan
Keyword(s):  
Oxidative Stress ◽  
Cardiac Hypertrophy ◽  
Cardiac Remodeling ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Ventricular Pressure ◽  
Expression Levels ◽  
Fructose Intake ◽  
Pregnancy And Lactation ◽  
And Oxidative Stress

Recent studies demonstrated that metabolic syndrome and cardiovascular diseases could be elicited by developmental programming, which is regulated by prenatal nutritional and environmental stress. In this study, we utilized a rat model to examine the effect of excessive maternal fructose intake during pregnancy and lactation on cardiac development and progression of pressure overload-induced cardiac hypertrophy in offspring. Transverse aortic constriction (TAC) was performed on 3-month-old male offspring to induce ventricular pressure overload. Four weeks post-TAC, echocardiographic assessment as well as histopathological and biochemical examinations were performed on the myocardium of the offspring. Echocardiographic and gross examinations showed that heart weight, interventricular septal thickness in diastole (IVD; d), and left ventricular posterior wall thickness in diastole (LVPW; d) were elevated in offspring with TAC and further increased by maternal fructose exposure (MFE). However, the left ventricular ejection function was not significantly affected. Myocardial histopathological examination revealed that the indices of fibrosis and oxidative stress were higher in offspring with MFE and TAC than those in animals receiving either treatment. Molecular examinations on the myocardium demonstrated an MFE-induced upregulation of p38-MAPK signaling. Next generation sequence (NGS) analysis indicated a modulation of the expression levels of several cardiac hypertrophy-associated genes, including GPR22, Myh7, Nppa, P2RX4, and Npy by MFE. Subsequent RT-PCR indicated that MFE regulated the expression levels of genes responsive to cardiac hypertrophy (i.e., Myh-7, ANP) and oxidative stress (i.e., GR, GPx, and NQO-1). In conclusion, MFE during pregnancy and lactation modulated myocardial gene expression, increased oxidative stress, and exacerbated ventricular pressure overload-induced cardiac remodeling in rat offspring.

Abstract 5394: H11 Kinase/Hsp22, A Novel Mechanism in the Transition to Heart Failure

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Hongyu Qiu ◽  
Chull Hong ◽  
Shumin Gao ◽  
Dorothy E Vatner ◽  
Stephen F Vatner ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Diastolic Pressure ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Lv Function ◽  
Area At Risk ◽  
Lung Weight ◽  
Tibial Length ◽  
Lv Ejection Fraction

H11 kinase/Hsp22 (H11K), a heat shock protein expressed mainly in the heart, is up-regulated upon pressure overload in animal models and in patients. Cardiac-specific over-expression of H11K in a transgenic model induces cardiac hypertrophy with normal function and cardioprotection against lethal ischemia. We tested the hypothesis that H11K deletion would accelerate the transition into heart failure (HF) following chronic pressure overload. An H11K knockout (KO) mouse was generated, which survives after birth with normal Mendelian distribution. In basal conditions (4/group), no differences were found between KO and wild type (WT) in terms of left ventricular (LV) mass (LV/tibial length: 4.6±0.3 vs 4.1±0.1, NS) or LV ejection fraction (69±3% vs 70±1%, NS). After two weeks aortic banding the KO mice, compared to WT, showed a slightly greater mass (LV/tibial length: 8.2±0.3 vs 7.0±0.4, P<0.05), impaired LV function (LV ejection fraction: 45±3% vs 62±5%, P<0.05), and signs of HF (lung weight/TL: 16.2±3 vs 7.7±0.4, P<0.05; LV end-diastolic pressure: 22±4 mmHg vs 7±4 mmHg, P<0.05). To test whether H11K participates in cardiac cell survival, both WT and KO mice were submitted to 30 min no-flow ischemia of the left anterior descending artery followed by 24 hours reperfusion and staining for the area-at-risk (AAR) and infarct size (IS). Whereas AAR was comparable between groups, the IS/AAR was more than doubled (P<0.01, n=3/group) in KO (61±2.8%) compared to WT (26±2.8%). Therefore, H11K deletion does not affect basal cardiac function but it precipitates the transition into HF following pressure overload, potentially by loss of H11K cardioprotective action. This research has received full or partial funding support from the American Heart Association, AHA National Center.

scholarly journals A Novel Alginate-Based Delivery System for the Prevention and Treatment of Pressure-Overload Induced Heart Failure

2021 ◽  
Vol 11 ◽  
Author(s):  
Ambrish Kumar ◽  
Marwa Belhaj ◽  
Donald J. DiPette ◽  
Jay D. Potts
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Cell Size ◽  
Delivery System ◽  
Umbilical Vein ◽  
Pressure Overload ◽  
Cardiac Cell ◽  
Cell Viability Assay ◽  
Lung Weight ◽  
And Oxidative Stress

Background: α-CGRP (alpha-calcitonin gene related peptide) is a cardioprotective neuropeptide. Our recent study demonstrated that the administration of native α-CGRP, using osmotic mini-pumps, protected against transverse aortic constriction (TAC) pressure-induced heart failure in mice. However, the short half-life of peptides and the non-applicability of osmotic pumps in humans limits the use of α-CGRP as a therapeutic agent for heart failure (HF). Here, we sought to comprehensively study a novel α-CGRP delivery system using alginate microcapsules to determine its bioavailability in vivo and to test for cardioprotective effects in HF mice.Methods: Native α-CGRP filled alginate microcapsules (200 µm diameter) were prepared using an electrospray method. The prepared alginate-α-CGRP microcapsules were incubated with rat cardiac H9c2 cells, mouse cardiac HL-1 cells, and human umbilical vein endothelial cells (HUVECs), and the cytotoxicity of the alginate-α-CGRP microcapsules was measured by a trypan-blue cell viability assay and a calcium dye fluorescent based assay. The efficacy of the alginate-α-CGRP microcapsules was tested in a TAC-pressure overload mouse model of heart failure. Male C57BL6 mice were divided into four groups: sham, sham-alginate-α-CGRP, TAC-only, and TAC-alginate-α-CGRP, and the TAC procedure was performed in the TAC-only and TAC-alginate-α-CGRP groups of mice to induce pressure-overload heart failure. After 2 or 15 days post-TAC, alginate-α-CGRP microcapsules (containing an α-CGRP dose of 6 mg/kg/mouse) were administered subcutaneously on alternate days, for 28 days, and echocardiography was performed weekly. After 28 days of peptide delivery, the mice were sacrificed and their hearts were collected for histological and biochemical analyses.Results: Our in vitro cell culture assays showed that alginate-α-CGRP microcapsules did not affect the viability of the cell lines tested. The alginate-α-CGRP microcapsules released their peptides for an extended period of time. Our echocardiography, biochemical, and histology data from HF mice demonstrated that the administration of alginate-α-CGRP microcapsules significantly improved all cardiac parameters examined in TAC-mice. When compared to sham mice, TAC significantly decreased cardiac functions (as determined by fraction shortening and ejection fraction) and markedly increased heart and lung weight, left ventricle (LV) cardiac cell size, cardiac apoptosis, and oxidative stress. In contrast, the administration of alginate-α-CGRP microcapsules significantly attenuated the increased heart and lung weight, LV cardiac cell size, apoptosis, and oxidative stress in TAC mice.Conclusion: Our results demonstrate that the encapsulation of α-CGRP in an alginate polymer is an effective strategy to improve peptide bioavailability in plasma and increase the duration of the therapeutic effect of the peptide throughout the treatment period. Furthermore, alginate mediates α-CGRP delivery, either prior to the onset or after the initiation of the symptom progression of pressure-overload, improves cardiac function, and protects hearts against pressure-induced HF.

The aging-induced hyperexcretion of glucose-dependent insulinotropic peptide is essential for the healthy cardiac remodeling by prevention of cardiac ceramide accumulation

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
Y Kureishi Bando ◽  
Y.R Remina ◽  
T.K Kamihara ◽  
K.N Nishimura ◽  
T.M Murohara
Keyword(s):  
Oxidative Stress ◽  
Ketone Bodies ◽  
Left Ventricular ◽  
Heart Weight ◽  
Lv Function ◽  
Cardiac Aging ◽  
Normal Left Ventricular ◽  
Insulinotropic Peptide ◽  
Ceramide Accumulation ◽  
And Oxidative Stress

Abstract Background Glucose-dependent insulinotropic peptide (GIP) is incretin hormone that is emerged as an important regulator of lipid metabolism. Fat intake induces hypersecretion of GIP that is involved in obesity and ectopic fat accumulation. Aging is another stimulant of GIP hypersecretion, which is suggested as a cause of “sarcopenic obesity in elderly”. In heart, aging is the known risk factor of HFpEF, of which typical characteristics is pathological cardiac hypertrophy induced by unknown cause(s). It remained uncertain whether any ectopic fat accumulation, such as cardiac steatosis may cause the aging-induced cardiac hypertrophy. Ceramide is one of the lipid metabolites that involves in apoptosis, inflammation, and stress responses, which are among the pathogenic components of heart failure. However, it remained unclear whether the ceramide may play any pathophysiological role in cardiac aging. Purpose We thus hypothesized whether cardiac aging may alter cardiac lipid metabolism and the GIP may play a regulatory role in the cardiac aging via modulating cardiac steatosis, particularly ceramide. Methods Mouse model of GIPR deficiency (GIPR-KO) was employed and cardiac evaluation of GIPR-KO and the age-matched wild type mice were performed. Results Aging (50w/o) induced GIP hypersecretion in control mice and their body and heart weight were 50% increased as compared to younger counterpart (10w/o). In contrast, the aging-induced increase rate in body and heart weight of GIPR-KO was significantly lower (22%). Aging also increased the circulating ketone bodies with increase in FGF21 expression in heart and, notably, there was no pathological increase in cardiac ceremide and oxidative stress with normal left-ventricular (LV) function (LVEF=82.2±1.8). In contrast, GIPR-KO exhibited pathological increase in cardiac ceramide without the elevation of the circulating ketone bodies. The younger GIPR-KO (10 w/o) exhibited normal left-ventricular (LV) function, however, the older mice (50 w/o) exhibited systolic LV dysfunction (LVEF=55.8±8.5) with increase in cardiac apoptosis and oxidative stress. Cardiac ceramide accumulation was increased in the aged normal mice, which was significantly higher in the aged GIPR-KO. Furthermore, GIPR-KO exhibited increase in cardiac fibrosis and oxidative stress, which were absent in the aged normal counterpart. Conclusion Aging increased circulating GIP level the leads to compensatory rise in the circulating ketone bodies without pathological increase in cardiac ceremide and related oxidative stress in heart. Loss of GIP signaling caused pathological increase in cardiac ceramide, leading to the aging-induced progression of systolic left-ventricular dysfunction. Collectively, we conclude that the aging-induced GIP hyperexcretion is essential for the aging-induced healthy cardiac remodeling by augmenting compensatory ketone body elevation. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): KAKEN-HI

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