Abstract 16161: GSK-3β Activates Autophagy and Protects Against Cardiac Aging Through Ulk1

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Peiyong Zhai ◽  
Akihiro Shirakabe ◽  
Takanobu Yamamoto ◽  
Yoshiyuki Ikeda ◽  
Bonaventure Magrys ◽  
...  
Keyword(s):  
Cardiac Fibrosis ◽  
Glycogen Synthase ◽  
Left Ventricular ◽  
Protective Mechanism ◽  
Cross Sectional ◽  
Cardiac Aging ◽  
Beneficial Effects ◽  
Stiffness Constant ◽  
Age Related ◽  
Gsk 3Β

Accumulating lines of evidence suggest that glycogen synthase kinase-3β (GSK-3β) is involved in aging. However, the effects of GSK-3β on cardiac aging and the underlying mechanisms remain to be elucidated. Autophagy, a protective mechanism in aging, decreases with age. We hypothesized that GSK-3β attenuates cardiac aging via Ulk1, a regulator of autophagy, and studied constitutively active GSK-3βS9A knock-in mice (βKI), GSK-3βS9A/Ulk1+/- bigenic mice (Bigenic), and GSK-3β+/- mice (βKO) up to 24 months (M) of age. Left ventricular (LV) weight/body weight (LVW/BW, mg/g) was not significantly different among wild-type mice (WT), βKI and βKO at 6M. It was lower in βKI (2.4±0.1, p<0.005) and higher in βKO (4.8±0.8, p<0.05) than in WT (3.8±0.2) at 24M. Cardiomyocyte cross-sectional area (CSA, μm2) was smaller in βKI (360±9, p<0.001) but bigger in βKO (540±11, p<0.01) than in WT (502±5) at 24M. The LVW/BW was greater (3.5±0.2, p<0.001) and the CSA was bigger (527±4, p<0.001) in Bigenic than in βKI at 24M. These data demonstrate that GSK-3β inhibits age-dependent cardiac hypertrophy via Ulk1. Cardiac fibrosis (%) was more in βKO (5.4±0.1, p<0.001) and less in βKI (2.4±0.1, p<0.001) than in WT (4.0±0.3) at 24M. There was much more fibrosis in Bigenic (5.5±0.6, p<0.001) than in βKI at 24M. These data show that GSK-3β reduces age-related cardiac fibrosis via Ulk1. LV end-systolic elastance (Ees, mmHg/μl) and chamber stiffness constant (CSC, μl-1) were not significantly different among WT, βKI, and βKO at 6M. At 24M, the Ees was lower in βKO (4±1, p<0.05) and higher in βKI (12±3, p<0.05) than in WT (7±0), and the CSC was higher in βKO (0.19±0.01, p<0.001) and lower in βKI (0.06±0.01, p<0.001) than in WT (0.14±0.01). The beneficial effects of GSK-3β on cardiac function were abolished in the Bigenic, indicating that GSK-3β prevents age-specific cardiac dysfunction via Ulk1. The level of p62, a protein degraded by autophagy, was lower in βKI and higher in βKO than in WT. The numbers of autophagosomes and autolysosomes were significantly greater in βKI/tfLC3 (tandem fluorescent mRFP-GFP-LC3) mice than in tfLC3 or βKI/tfLC3/Ulk1+/- mice. These data suggest that GSK-3β activates autophagy via Ulk1. In conclusion, GSK-3β attenuates cardiac aging by activating Ulk1-dependent autophagy.

Abstract 12999: Senescence Marker Protein 30 Protect the Cardiac Injury From After Ischemia Reperfusion

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Shinpei Kadowaki ◽  
Tetsuro Shishido ◽  
Taro Narumi ◽  
Yuki Honda ◽  
Satoshi Nishiyama ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Acute Myocardial Infarction ◽  
Glycogen Synthase ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Marker Protein ◽  
Age Related ◽  
Ribosomal S6 Kinase ◽  
Gsk 3Β

Background: Successful myocardial reperfusion is effective therapy for improving the clinical outcome after acute myocardial infarction, nevertheless reperfusion injury can paradoxically induces cardiomyocyte dysfunction. Moreover, recovery of cardiac function is impaired with aging. Glycogen synthase kinase-3β (GSK-3β) and p70 ribosomal S6 kinase (p70S6K) are cardioprotective against I/R via mitochondrial dysfunction. Senescence marker protein-30 (SMP30), which regulates mitochondrial quality and decreases with aging, is an organ-protective protein; however the protective role of SMP30 against ischemia/reperfusion (I/R) has not been clearly determined yet. Methods and Result: Firstly, we confirmed that SMP30 expressions in the heart were progressively decreased with aging. In vitro study, we also found that reactive oxygen species decreased expression levels of SMP30 in neonatal cardiomyocyte. Depletion of SMP30 increased apoptotic cardiomyocyte death after hydrogen peroxide stimulation. To evaluate the cardioprotective role of SMP30, we induced 30 min ischemia and 24-hr reperfusion (I/R) in WT and SMP30 KO mice. Phosphorylation levels of p70S6K and GSK-3β in the heart were increased after IR in WT mice; however those phosphorylation were attenuated in SMP30 KO mice. SMP30 KO mice after I/R had significantly larger numbers of apoptotic cardiomyocyte than WT mice ( 10.5± 5.7% vs. 4.0± 1.7%, p < 0.05), that correlated with a significant expansion in infarct size and a significant reduction of left ventricular fractional shortening (37.3± 4.3% vs 43.4± 5.1%, p < 0.01). Conclusions: These results suggest that reduction of SMP30 levels with aging is associated with age-related dysfunction after ischemia-reperfusion through disability to phosphorylate p70S6K and GSK-3β. Thus, SMP30 might be a novel therapeutic target for the treatment of acute myocardial infarction in elderly patient.

Abstract 314: Inactivation-Resistant GSK3αβ Dual Isoform Expression Attenuates Isoproterenol-Induced Myocardial Hypertrophy and Preserves Cardiac Function

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Ian G Webb ◽  
Yasuhiro Nishino ◽  
James E Clark ◽  
Colin E Murdoch ◽  
Ajay M Shah ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Glycogen Synthase ◽  
Interstitial Fibrosis ◽  
Left Ventricular ◽  
Heart Weight ◽  
Age Related ◽  
Ventricular Wall Thickness ◽  
Isoform Expression ◽  
Gsk 3Β ◽  
Opposing Effects

Glycogen synthase kinase-3 (GSK-3) is implicated as an important signalling mediator in normal developmental myocardial growth and adverse hypertrophic remodelling. Upstream phosphorylation of isoform specific N-terminal serine residues - ser21(GSK-3α) and ser9(GSK-3β), respectively - inhibits kinase activity. Opposing effects of the two isoforms have recently been described in response to hypertrophic stimuli, but little is known of the overall effect of dual-isoform manipulation. We set out to characterise baseline and isoproterenol (ISO) stimulated phenotypes of mice with inactivation-resistant GSK-3αβ knockin (KI) alleles, in which ser21/9 are converted to non-phosphorylatable alanine. Between 5–15 weeks there was a non-significant trend towards higher heart weight (HW): body weight (BW) ratios in KI mice versus wild type (WT) mice. Mean left ventricular wall thickness (LVWT) at the level of the papillary muscle was comparable between genotypes (1.3±0.2mm vs 1.6±0.2mm, ns, n=8). 8–10 week old weight-matched mice received 2 weeks subcutaneous ISO (30mg/kg/d) or control saline (Con) infusions. WT hearts hypertrophied with ISO (LVWT 1.9±0.1mm vs 1.3±0.2mm Con, n=8; HW:BW ratio 6.7±0.6 vs 5.4±0.4 Con, n=10, both p< 0.05), but KI mice did not (1.4±0.1mm vs 1.6±0.2mm KI Con; HW:BW 6.2±1.0 vs 6.1±0.6 KI Con, respectively, both ns). Hypertrophy in the WT hearts was associated with reduced LV ejection fraction (41±9% vs 63±5% Con, n=6, p< 0.05) and greater interstitial fibrosis (2.1±0.5% vs 0.8±0.6%, n=6, p< 0.05). These were both attenuated in the KI mice subjected to ISO (70±13% vs 64±11% Con, and 1.3±0.7% vs 0.8±0.3% Con, respectively, both ns). GSK-3 inhibition with daily intraperitoneal 6-bromoindirubin-3′-oxime restored hypertrophic sensitivity to ISO in the KI mice (LVWT 1.8±0.2mm; HW:BW 7.3±0.5, p< 0.05 for both groups vs KI + ISO alone) but had no effect in the absence of hypertrophic stimulus (1.4±0.2mm and 5.4±0.7, respectively, for KI + Con + Bio, ns vs KI + Con alone). In conclusion, inactivation-resistant GSK-3αβ dual isoform expression does not affect age-related (eutrophic) myocardial growth in the mouse. However, it protects against pathological growth, maintaining cardiac function and attenuating interstitial fibrosis.

Abstract P471: Mechanisms Controlling Regression Of Cardiac Fibrosis By Removal Of Pressure Overload

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Lily Neff ◽  
An Van Laer ◽  
Catalin F Baicu ◽  
Michael R Zile ◽  
Amy Bradshaw
Keyword(s):  
Cardiac Fibrosis ◽  
Volume Fraction ◽  
Lysyl Oxidase ◽  
Cardiac Fibroblasts ◽  
Pressure Overload ◽  
Left Ventricular Pressure ◽  
Left Ventricular ◽  
Cellular Mechanisms ◽  
Cross Sectional ◽  
Fibroblast Activation

Background: Antecedent conditions, like aortic stenosis, can induce left ventricular pressure overload (LVPO), that can lead to Heart Failure with Preserved Ejection Fraction (HFpEF). Myocardial fibrosis and stiffness are key characteristics of HFpEF. Cardiac fibroblasts are the primary cell type regulating ECM production and deposition. In previous studies, biopsies isolated at the time of SAVR surgery, to correct stenosis, and then at 1-year and 5-years post-SAVR showed reductions in hypertrophy and fibrosis demonstrating these processes can regress. However, cellular mechanisms, including fibroblast activity, are poorly defined. Objective: Define mechanisms that contribute to remodeling of ECM before and after LVPO. Methods: LVPO was induced using transverse aortic constriction (TAC). LVPO was relieved by removal of the band (unTAC) at 4 wks. Cardiomyocyte cross-sectional area (CSA), collagen volume fraction (CVF), and protein production was measured by histology and immunoblot for five time points: nonTAC, 2wk TAC, 4wk TAC, 4wk TAC+2wk unTAC, and 4wk TAC+4wk unTAC. Results: In response to LVPO, myocyte CSA increased by 23% at 2wk TAC and by 47% at 4wk. CVF increased by 64% and 204% at 2wk and 4wk TAC, respectively, versus nonTAC. In 2wk TAC hearts, SMA, a marker of fibroblast activation was increased as was production of two collagen cross-linking enzymes, lysyl oxidase (LOX) and LOXL2, in the absence of significant increases in markers of ECM degradation. After unloading, myocyte CSA decreased by 20% in 2wk unTAC versus 4wk TAC and CVF decreased by 38% in 4wk unTAC versus 4wk TAC. Coincident with decreases in CVF, levels of pro-MMP2 increased at 2wk unTAC as did levels of degraded collagen measured by collagen hybridizing peptide reactivity. Whereas markers of ECM deposition, LOX and LOXL2, were not increased in unTAC myocardium, a resurgence of SMA production occurred in 2wk unTAC. Conclusions: In LVPO hearts, hypertrophy was characterized by increases in myocyte CSA, greater CVF, and fibroblast activation with increased production of pro-fibrotic ECM. After unloading, hypertrophy and fibrosis significantly decreased accompanied by increases in ECM degrading activity and reductions in proteins that contribute to collagen assembly.

scholarly journals Caloric restriction: powerful protection for the aging heart and vasculature

2011 ◽  
Vol 301 (4) ◽  
pp. H1205-H1219 ◽  
Author(s):  
Edward P. Weiss ◽  
Luigi Fontana
Keyword(s):  
Arterial Stiffness ◽  
Cardiovascular System ◽  
Current Knowledge ◽  
Left Ventricular Diastolic Function ◽  
The United States ◽  
Left Ventricular ◽  
Cvd Risk ◽  
Beneficial Effects ◽  
Age Related ◽  
Increased Risk

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in the United States. Research has shown that the majority of the cardiometabolic alterations associated with an increased risk of CVD (e.g., insulin resistance/type 2 diabetes, abdominal obesity, dyslipidemia, hypertension, and inflammation) can be prevented, and even reversed, with the implementation of healthier diets and regular exercise. Data from animal and human studies indicate that more drastic interventions, i.e., calorie restriction with adequate nutrition (CR), may have additional beneficial effects on several metabolic and molecular factors that are modulating cardiovascular aging itself (e.g., cardiac and arterial stiffness and heart rate variability). The purpose of this article is to review the current knowledge on the effects of CR on the aging of the cardiovascular system and CVD risk in rodents, monkeys, and humans. Taken together, research shows that CR has numerous beneficial effects on the aging cardiovascular system, some of which are likely related to reductions in inflammation and oxidative stress. In the vasculature, CR appears to protect against endothelial dysfunction and arterial stiffness and attenuates atherogenesis by improving several cardiometabolic risk factors. In the heart, CR attenuates age-related changes in the myocardium (i.e., CR protects against fibrosis, reduces cardiomyocyte apoptosis, prevents myosin isoform shifts, etc.) and preserves or improves left ventricular diastolic function. These effects, in combination with other benefits of CR, such as protection against obesity, diabetes, hypertension, and cancer, suggest that CR may have a major beneficial effect on health span, life span, and quality of life in humans.

Profound cardioprotection with timolol in a female rat model of aging-related altered left ventricular function

2011 ◽  
Vol 89 (4) ◽  
pp. 277-288 ◽  
Author(s):  
Nazli N. Sozmen ◽  
Erkan Tuncay ◽  
Ayca Bilginoglu ◽  
Belma Turan
Keyword(s):  
Antioxidant System ◽  
Ventricular Myocytes ◽  
Heart Function ◽  
Thioredoxin Reductase ◽  
Left Ventricular ◽  
Female Rats ◽  
Male Rats ◽  
Female Rat ◽  
Beneficial Effects ◽  
Age Related

Increasing evidence shows a marked beneficial effect with β-blockers in heart dysfunction via scavenging reactive oxygen species. Previously we showed that chronic treatment with either timolol or propranolol possessed similar beneficial effects for heart function in male rats as age increased, whereas only timolol exerted similar benefits in female rats. Therefore, in this study, we aimed first to examine the cellular bases for age-related alterations in excitation–contraction coupling in ventricular myocytes from female rats and, second, to investigate the hypothesis that age-related changes in [Ca2+]ihomeostasis and receptor-mediated system can be prevented with chronic timolol treatment. Chronic timolol treatment of 3-month-old female rats abolished age-related decrease in left ventricular developed pressure and the attenuated responses to β-adrenoreceptor stimulation. It also normalized the altered parameters of [Ca2+]itransients, decreased Ca2+loading of sarcoplasmic reticulum and increased basal [Ca2+]i, and decreased L-type Ca2+currents in 12-month-old female rats compared with the 3-month-old group. Adenylyl cyclase activity, β-adrenoreceptor affinity to its agonist, and β-adrenoreceptor density of the 12-month-old group are normalized to those of the 3-month-old group. Moreover, timolol treatment prevented dysfunction of the antioxidant system, including increased lipid peroxidation, decreased ratio of reduced glutathione to oxidized glutathione, and decreased activities of thioredoxin reductase and glucose-6-phosphate dehydrogenase, in the left ventricle of hearts from the 12-month-old group. Our data confirmed that aging-related early myocardial impairment is primarily related to a dysfunctional antioxidant system and impairment of Ca2+homeostasis, which can be prevented with chronic timolol treatment.

scholarly journals GSK-3β heterozygous knockout is cardioprotective in a knockin mouse model of familial dilated cardiomyopathy

2016 ◽  
Vol 310 (11) ◽  
pp. H1808-H1815 ◽  
Author(s):  
Rasha M. S. M. Mohamed ◽  
Sachio Morimoto ◽  
Islam A. A. E.-H. Ibrahim ◽  
Dong-Yun Zhan ◽  
Cheng-Kun Du ◽  
...  
Keyword(s):  
Mouse Model ◽  
Dilated Cardiomyopathy ◽  
Glycogen Synthase ◽  
Troponin T ◽  
Systolic Function ◽  
Left Ventricular Systolic Function ◽  
Left Ventricular ◽  
Myosin Heavy Chain Isoform ◽  
Familial Dilated Cardiomyopathy ◽  
Gsk 3Β

Glycogen synthase kinase-3β (GSK-3β) plays a central role in both cardiac physiology and pathology. Herein we want to clarify the role of GSK-3β in familial dilated cardiomyopathy. We generated a mouse model carrying a heterozygous knockout mutation of GSK-3β (GSK-3β+/− KO), together with a ΔK210 knockin mutation in cardiac troponin T (ΔK210 cTnT KI), which was proved to be one of the genetic causes of familial dilated cardiomyopathy (DCM). GSK-3β+/− KO prevented the slow and rapid deterioration in left ventricular systolic function accompanying heart failure (HF) in DCM mice with heterozygous and homozygous ΔK210 cTnT KI mutations, respectively. GSK-3β+/− KO also prevented cardiac enlargement, myocardial fibrosis, and cardiomyocyte apoptosis and markedly reduced the expression of cardiac β-myosin heavy chain isoform, indicative of HF, in DCM mice with homozygous ΔK210 cTnT KI mutation. GSK-3β+/− KO also extended the life span of these DCM mice. This study suggests that the inhibition of GSK-3β is cardioprotective in familial DCM associated with ΔK210 cTnT mutation.

Abstract P409: GSK-3β Deficiency In Cardiomyocyte Induces Cardiac Progenitor Cell Proliferation In The Ischemic Heart

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Ayesha Yusuf ◽  
Rizwan Qaisar ◽  
James R Woodgett ◽  
Firdos Ahmad
Keyword(s):  
Cell Proliferation ◽  
Glycogen Synthase ◽  
Contractile Function ◽  
Left Ventricular ◽  
Ischemic Heart ◽  
Stem Cell Marker ◽  
Cardiomyocyte Proliferation ◽  
Littermate Control ◽  
Gsk 3Β ◽  
Immunofluorescence Labeling

The cardiomyocytes are terminally differentiated cells and ischemia-induced cardiomyopathy is an irreparable loss. Novel strategies are needed to induce resident cardiac progenitor cells (CPCs) proliferation in situ to enhance the possibility of cardiac regeneration. Here we sought to identify a potential role for glycogen synthase kinase-3β (GSK-3β), a critical regulator of cell proliferation and differentiation, in CPCs proliferation in the ischemic heart. Cardiomyocyte-specific conditional GSK-3β knockout (cKO) and littermate control mice were recruited and challenged with myocardial infarction (MI). The cardiac function was assessed using trans-thoracic M-mode echocardiography. The level of CPC proliferation in the ischemic cKO hearts was determined at 2, 4 and 8 weeks post-MI through immunofluorescence labeling of stem cell marker c-Kit. To confirm the lineage of identified c-Kit -positive cells (KPCs) in the heart, a hematopoietic lineage marker was stained along with c-Kit. The cardiac left ventricular chamber dimension (LVID) and contractile functions were comparable until 2 weeks post-MI. The cKO mice displayed significantly preserved LV chamber [LVIDd(mm); 5.01±0.67 vs.6.09±0.65, p =0.01] and contractile function [LVEF(%); 31.98±8.52 vs. 18.06±7.11., p =0.01] in comparison to control mice at 4 week post-MI. Consistent with protective phenotypes, an increased percentage of KPC was observed in the cKO hearts at 4 and 6-weeks post-MI which was accompanied by an increased level of cardiomyocyte proliferation. Further analysis revealed that the observed increased number of KPCs in the ischemic cKO hearts were mostly from a cardiac lineage as the majority of identified KPCs were negative for the hematopoietic marker, CD45. In conclusion, our findings strongly suggest that GSK-3β inhibits CPCc proliferation post-ischemia, and loss of GSK-3β in cardiomyocytes promotes resident CPCc proliferation potentially through paracrine mechanisms.

scholarly journals And the beat goes on: maintained cardiovascular function during aging in the longest-lived rodent, the naked mole-rat

2014 ◽  
Vol 307 (3) ◽  
pp. H284-H291 ◽  
Author(s):  
Kelly M. Grimes ◽  
Anilkumar K. Reddy ◽  
Merry L. Lindsey ◽  
Rochelle Buffenstein
Keyword(s):  
Cardiovascular Function ◽  
Left Ventricular ◽  
Lv Function ◽  
Cross Sectional ◽  
Arterial Stiffening ◽  
Functional Changes ◽  
Age Related ◽  
Mole Rat ◽  
Naked Mole Rat ◽  
Negligible Senescence

The naked mole-rat (NMR) is the longest-lived rodent known, with a maximum lifespan potential (MLSP) of >31 years. Despite such extreme longevity, these animals display attenuation of many age-associated diseases and functional changes until the last quartile of their MLSP. We questioned if such abilities would extend to cardiovascular function and structure in this species. To test this, we assessed cardiac functional reserve, ventricular morphology, and arterial stiffening in NMRs ranging from 2 to 24 years of age. Dobutamine echocardiography (3 μg/g ip) revealed no age-associated changes in left ventricular (LV) function either at baseline or with exercise-like stress. Baseline and dobutamine-induced LV pressure parameters also did not change. Thus the NMR, unlike other mammals, maintains cardiac reserve with age. NMRs showed no cardiac hypertrophy, evidenced by no increase in cardiomyocyte cross-sectional area or LV dimensions with age. Age-associated arterial stiffening does not occur since there are no changes in aortic blood pressures or pulse-wave velocity. Only LV interstitial collagen deposition increased 2.5-fold from young to old NMRs ( P < 0.01). However, its effect on LV diastolic function is likely minor since NMRs experience attenuated age-related increases in diastolic dysfunction in comparison with other species. Overall, these findings conform to the negligible senescence phenotype, as NMRs largely stave off cardiovascular changes for at least 75% of their MLSP. This suggests that using a comparative strategy to find factors that change with age in other mammals but not NMRs could provide novel targets to slow or prevent cardiovascular aging in humans.

scholarly journals Cardiomyocyte GSK-3β deficiency induces cardiac progenitor cell proliferation in the ischemic heart through paracrine mechanisms

2021 ◽  
Author(s):  
Ayesha M. Yusuf ◽  
Rizwan Qaisar ◽  
Abaher O. Al-Tamimi ◽  
Manju Nidagodu Jayakumar ◽  
James Robert Woodgett ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Growth Factors ◽  
Progenitor Cell ◽  
Glycogen Synthase ◽  
Contractile Function ◽  
Cardiac Regeneration ◽  
Left Ventricular ◽  
Cardiac Progenitor Cell ◽  
Gsk 3Β

Cardiomyopathy is an irreparable loss and novel strategies are needed to induce resident cardiac progenitor cell (CPC) proliferation in situ to enhance the possibility of cardiac regeneration. Here we identify a potential role for glycogen synthase kinase-3β (GSK-3β), a critical regulator of cell proliferation and differentiation, in CPC proliferation that occurs after myocardial infarction (MI). Cardiomyocyte-specific conditional GSK-3β knockout (cKO) and littermate control mice were employed and challenged with MI. Though cardiac left ventricular chamber dimension (LVID) and contractile functions were comparable at two week post-MI, cKO mice displayed significantly preserved LV chamber and contractile function vs. control mice at four-weeks post-MI. Consistent with protective phenotypes, an increased percentage of c-kit positive cells (KPCs) were observed in the cKO hearts at four and six weeks post-MI which was accompanied by increased levels of cardiomyocyte proliferation. Further analysis revealed that the observed increased number of KPCs in the ischemic cKO hearts was mainly from a cardiac lineage as the majority of identified KPCs were negative for the hematopoietic marker, CD45. Mechanistically, cardiomyocyte-GSK-3β profoundly suppresses the expression of growth factors (GFs), including basic-FGF angiopoietin-2, erythropoietin, stem cell factor (SCF), PDGF-BB, G-CSF, and VEGF, post-hypoxia. In conclusion, our findings strongly suggest that loss of cardiomyocyte-GSK-3β promotes cardiomyocyte and resident CPC proliferation post-MI. The induction of cardiomyocytes and CPC proliferation in the ischemic cKO hearts is potentially regulated by autocrine and paracrine signaling governed by dysregulated growth factors post-MI. A strategy to inhibit cardiomyocyte GSK-3β could be helpful for promotion of in-situ cardiac regeneration post-MI injury.

scholarly journals Increased ADAMTS1 mediates SPARC-dependent collagen deposition in the aging myocardium

2016 ◽  
Vol 310 (11) ◽  
pp. E1027-E1035 ◽  
Author(s):  
Hiroe Toba ◽  
Lisandra E. de Castro Brás ◽  
Catalin F. Baicu ◽  
Michael R. Zile ◽  
Merry L. Lindsey ◽  
...  
Keyword(s):  
Cardiac Fibrosis ◽  
Transforming Growth Factor ◽  
Collagen I ◽  
Matricellular Protein ◽  
Dependent Manner ◽  
Collagen Deposition ◽  
Middle Aged ◽  
Cardiac Aging ◽  
Cellular Expression ◽  
Age Related

Secreted protein acidic and rich in cysteine (SPARC) is a collagen-binding matricellular protein highly expressed during fibrosis. Fibrosis is a prominent component of cardiac aging that reduces myocardial elasticity. Previously, we reported that SPARC deletion attenuated myocardial stiffness and collagen deposition in aged mice. To investigate the mechanisms by which SPARC promotes age-related cardiac fibrosis, we evaluated six groups of mice ( n = 5–6/group): young (3–5 mo old), middle-aged (10–12 mo old), and old (18–29 mo old) C57BL/6 wild type (WT) and SPARC-null (Null) mice. Collagen content, determined by picrosirius red staining, increased in an age-dependent manner in WT but not in Null mice. A disintegrin and metalloproteinase with thrombospondin-like motifs 1 (ADAMTS1) increased in middle-aged and old WT compared with young, whereas in Null mice only old animals showed increased ADAMTS1 expression. Versican, a substrate of ADAMTS1, decreased with age only in WT. To assess the mechanisms of SPARC-induced collagen deposition, we stimulated cardiac fibroblasts with SPARC. SPARC treatment increased secretion of collagen I and ADAMTS1 (both the 110-kDa latent and 87-kDa active forms) into the conditioned media as well as the cellular expression of transforming growth factor-β1-induced protein (Tgfbi) and phosphorylated Smad2. An ADAMTS1 blocking antibody suppressed the SPARC-induced collagen I secretion, indicating that SPARC promoted collagen production directly through ADAMTS1 interaction. In conclusion, ADAMTS1 is an important mediator of SPARC-regulated cardiac aging.

Sign in / Sign up

Export Citation Format

Share Document