Cardiac-specific ablation of theSTAT3gene in the subacute phase of myocardial infarction exacerbated cardiac remodeling

2015 ◽  
Vol 309 (3) ◽  
pp. H471-H480 ◽  
Author(s):  
Daichi Enomoto ◽  
Masanori Obana ◽  
Akimitsu Miyawaki ◽  
Makiko Maeda ◽  
Hiroyuki Nakayama ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Remodeling ◽  
Cardiac Fibrosis ◽  
Biological Significance ◽  
Weight Ratio ◽  
Fluorescence Analysis ◽  
Border Zone ◽  
Intrinsic Activity ◽  
Heart Weight ◽  
Subacute Phase

STAT3 is a cardioprotective molecule against acute myocardial injury; however, recent studies have suggested that chronic STAT3 activation in genetically modified mice was detrimental after myocardial infarction (MI). In the present study, we assessed the biological significance of STAT3 activity in subacute MI using tamoxifen (TM)-inducible cardiac-specific STAT3 knockout (STAT3 iCKO) mice. After coronary ligation, STAT3 was rapidly activated in hearts, and its activation was sustained to the subacute phase. To make clear the pathophysiological roles of STAT3 activation specifically in subacute MI, MI was generated in STAT3 iCKO mice followed by TM treatment for 14 consecutive days beginning from day 11 after MI, which ablated the STAT3 gene in the subacute phase. Intriguingly, mortality was increased by TM treatment in STAT3 iCKO mice, accompanied by an increased heart weight-to-body weight ratio. Masson's trichrome staining demonstrated that cardiac fibrosis was dramatically exacerbated in STAT3 iCKO mice 24 days after MI (fibrotic circumference: 58.3 ± 6.7% in iCKO mice and 40.8 ± 9.3% in control mice), concomitant with increased expressions of fibrosis-related gene transcripts, including matrix metalloproteinase 9, procollagen 1, and procollagen 3. Echocardiography clarified that cardiac function was deteriorated in STAT3 iCKO mice (fractional shortening: 20.6 ± 4.1% in iCKO mice and 29.1 ± 6.0% in control mice). Dihydroethidium fluorescence analysis revealed that superoxide production was increased in STAT3 iCKO mice. Moreover, immunohistochemical analyses revealed that capillary density was decreased in STAT3 iCKO mice. Finally, STAT3 deletion in subacute MI evoked severe cardiac hypertrophy in the border zone. In conclusion, the intrinsic activity of STAT3 in the myocardium confers the resistance to cardiac remodeling in subacute MI.

Abstract 12354: Cardiac STAT3 Activation in Subacute Phase of Myocardial Infarction was Required for the Suppression of Adverse Cardiac Remodeling

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Daichi Enomoto ◽  
Masanori Obana ◽  
Akimitsu Miyawaki ◽  
Tomomi Mohri ◽  
Makio Maeda ◽  
...  
Keyword(s):  
Cardiac Remodeling ◽  
Biological Significance ◽  
Chronic Phase ◽  
Capillary Density ◽  
Acute Injury ◽  
Heart Weight ◽  
Cardiac Damage ◽  
Subacute Phase ◽  
Time Specific ◽  
The Impact

Backgroud: Cardiac STAT3 plays crucial roles in cardioprotection against acute injury after MI. However, mutated gp130-induced continuous STAT3 activation resulted in serious cardiac damage in the subacute phase of MI. Here, we examined the biological significance of intrinsic cardiac STAT3 during subacute/chronic phase of MI in a time specific manner using tamoxifen inducible cardiac specific STAT3 knockout mice (iCKO). Methods and Results: MI was generated by ligating the left coronary artery in mice. Immunoblotting revealed that STAT3 was rapidly activated in the myocardium, and that its activation was sustained to subacute phase after MI. To clarify the impact of cardiac STAT3 in subacute phase of MI, STAT3 gene was ablated by administering tamoxifen to α-MHC-MerCreMer/STAT3 flox/flox for 14 consecutive days from post-infarct day 11. As control mice, α-MHC-MerCreMer/STAT3 wild/wild mice were used. Importantly, MI-induced cardiac STAT3 activation was significantly decreased in iCKO mice at day 24. Intriguingly, the mortality was accelerated in iCKO mice compared with control mice, coincident with increased heart weight/body weight. Masson’s trichrome staining demonstrated that cardiac STAT3 ablation resulted in severe fibrosis (iCKO; 58.3±6.7%, control; 40.8±9.3%, p <0.01, n=7 for control, n=8 for iCKO). Moreover, Echocardiography clarified that cardiac function was deteriorated in iCKO mice (FS: iCKO; 20.6±4.1%, control; 29.1±6.0%, p <0.05, n=10 for control, n=11 for iCKO). In border area, marked myocardial injuries, including ROS production and hypertrophy, were observed in iCKO mice. Finally, immunohistochemistry revealed that capillary density was decreased in iCKO mice (iCKO; 1724.2±119.4 capillaries/mm 2 , control; 2110.5±77.7 capillaries/mm 2 , p <0.01, n=30 fields from 5 mice for each). Conclusions: Cardiac STAT3 ablation in subacute phase of MI aggravated cardiac remodeling. The augmentation of STAT3 activity could be a therapeutic strategy for the prevention from the onset of chronic heart failure.

Abstract 9905: Myeloid Cell Derived Leucine Rich α2 Glycoprotein Attenuates Adverse Cardiac Remodeling After Myocardial Infarction

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Shohei Kumagai ◽  
Hiroyuki Nakayama ◽  
Minoru Fujimoto ◽  
Hiromi Honda ◽  
Satoshi Serada ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Bone Marrow ◽  
Cardiac Remodeling ◽  
Cardiac Fibrosis ◽  
Bone Marrow Cells ◽  
Myeloid Cells ◽  
Immunohistochemical Analysis ◽  
Vessel Density ◽  
Border Zone ◽  
Serum Biomarker

Background: Leucine rich α2 glycoprotein (LRG), a member of the leucine-rich repeat family, was isolated from human plasma. Recently, LRG has been identified as a novel serum biomarker for various inflammatory diseases. It was also reported that serum LRG concentrations was strongly correlated with B-type natriuretic peptide in patients with heart failure. However, its pathophysiological roles in hearts after myocardial infarction (MI) remain to be elucidated. Objective: To determine the functional roles of LRG in cardiac remodeling after MI. Methods and Results: Murine MI was generated by ligating the left coronary artery. The expression of LRG was increased in hearts after MI. Immunofluorescence microscopic and flow cytometric analyses revealed that LRG was mainly produced by CD11b-positive myeloid cells in post-infarct myocardium. To elucidate pathophysiological roles of LRG in heart, we generated MI in wild-type (WT) and LRG-knockout (KO) mice. At day 14 after MI, cardiac fibrosis and dysfunction were aggravated in KO mice compared to WT mice (fibrotic area/ LV area: WT: 34.1 ± 7.2%, KO: 46.5 ± 12.8% n=10-16, p<0.01) (fractional shortening: WT: 34.8±7.1%, KO: 24.3±7.0%, n=6-9, p<0.01). Immunohistochemical analysis demonstrated that CD31-positive vessel density decreased at border zone in KO mice compared to WT mice 14 days after MI (vessel density: WT: 2740±190/mm2, KO: 2183±293/mm2 n=10-16, p<0.01). We explored the mechanism of LRG-mediated angiogenesis in post-infarct myocardium, and found that the activation of smad1/5/8, a pro-angiogenic signaling pathway, was attenuated in KO mice. Accompanied by impaired angiogenesis, cardiomyocytes apoptosis was increased in KO mice compared to WT mice at subacute phase after MI. Finally, bone marrow chimera experiments showed that bone marrow cells-derived LRG rescued adverse cardiac remodeling in KO mice, accompanied by restoration of capillary density. Conclusion: LRG was mainly produced by heart-infiltrated myeloid cells, and suppressed adverse cardiac remodeling after MI through enhanced angiogenesis. In this study, LRG was defined as a novel cardioprotective factor. Thus, LRG could be not only a serum biomarker but also a therapeutic target in cardiovascular diseases.

scholarly journals OSM Enhances Angiogenesis and Improves Cardiac Function after Myocardial Infarction

2015 ◽  
Vol 2015 ◽  
pp. 1-10
Author(s):  
Xiaotian Zhang ◽  
Di Zhu ◽  
Liping Wei ◽  
Zhijing Zhao ◽  
Xin Qi ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Body Weight ◽  
Cardiac Function ◽  
Weight Ratio ◽  
Oncostatin M ◽  
Border Zone ◽  
Heart Weight ◽  
Vehicle Group ◽  
Infarct Border Zone ◽  
Infarct Border

Oncostatin M (OSM) has been reported to stimulate angiogenesis by upregulating VEGF and bFGF, implying that it could be a therapeutic strategy in treating ischemic diseases. The present study was aimed at investigating whether OSM could improve cardiac function via prompting angiogenesis following myocardial infarction (MI). Wild type (WT) and Oβknock-out (Oβ−/−) mice were, respectively, randomized into sham group, MI + vehicle group, and MI + OSM group. WT mice displayed significantly impaired cardiac function after MI. OSM treatment attenuated cardiac dysfunction in WT MI mice, while Oβdeletion abrogated the protective effects. Besides, OSM attenuated heart hypertrophy and pulmonary congestion evidenced by decreased heart weight/body weight and lung weight/body weight ratio. Further, reduction of apoptosis and fibrosis in infarct border zone was observed in OSM treated WT MI mice compared with vehicle. Moreover, in WT mice subjected to MI, OSM treatment significantly increased capillary density along with upregulation of p-Akt and angiogenic factors VEGF and bFGF in comparison with vehicle, and this phenomenon was not found in Oβ−/−mice. In conclusion, OSM treatment preserved cardiac function, inhibited apoptosis and fibrosis, and stimulated angiogenesis via upregulating VEGF and bFGF in infarct border zone of ischemic myocardium, indicating that OSM could be a novel therapeutic target for MI.

scholarly journals Cardiac phosphatase-deficient 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase increases glycolysis, hypertrophy, and myocyte resistance to hypoxia

2008 ◽  
Vol 294 (6) ◽  
pp. H2889-H2897 ◽  
Author(s):  
Qianwen Wang ◽  
Rajakumar V. Donthi ◽  
Jianxun Wang ◽  
Alex J. Lange ◽  
Lewis J. Watson ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Cardiac Fibrosis ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Weight Ratio ◽  
Cardiac Metabolism ◽  
Heart Weight ◽  
Acid Oxidation ◽  
Important Regulator

During ischemia and heart failure, there is an increase in cardiac glycolysis. To understand if this is beneficial or detrimental to the heart, we chronically elevated glycolysis by cardiac-specific overexpression of phosphatase-deficient 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFK-2) in transgenic mice. PFK-2 controls the level of fructose-2,6-bisphosphate (Fru-2,6-P2), an important regulator of phosphofructokinase and glycolysis. Transgenic mice had over a threefold elevation in levels of Fru-2,6-P2. Cardiac metabolites upstream of phosphofructokinase were significantly reduced, as would be expected by the activation of phosphofructokinase. In perfused hearts, the transgene caused a significant increase in glycolysis that was less sensitive to inhibition by palmitate. Conversely, oxidation of palmitate was reduced by close to 50%. The elevation in glycolysis made isolated cardiomyocytes highly resistant to contractile inhibition by hypoxia, but in vivo the transgene had no effect on ischemia-reperfusion injury. Transgenic hearts exhibited pathology: the heart weight-to-body weight ratio was increased 17%, cardiomyocyte length was greater, and cardiac fibrosis was increased. However, the transgene did not change insulin sensitivity. These results show that the elevation in glycolysis provides acute benefits against hypoxia, but the chronic increase in glycolysis or reduction in fatty acid oxidation interferes with normal cardiac metabolism, which may be detrimental to the heart.

Abstract 327: Apelin-13 Increases Myocardial Progenitor Cells and Improves Myocardial Remodeling of Post-myocardial Infarction.

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
lanfang Li ◽  
Heng Zeng ◽  
Jian-Xiong Chen
Keyword(s):  
Myocardial Infarction ◽  
Progenitor Cells ◽  
Cardiac Remodeling ◽  
Cardiac Fibrosis ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Cxcr4 Expression ◽  
Post Myocardial Infarction ◽  
Coronary Artery Ligation ◽  
Vascular Progenitor Cells

ABSTRACT: Apelin is an endogenous ligand for the angiotensin-like 1 receptor (APJ) and has beneficial effects against hypertension and myocardial ischemia/reperfusion injury. Little is known about the role of apelin in the homing of vascular progenitor cells (PCs) and cardiac remodeling post-myocardial infarction (MI). The present study investigates whether apelin affects PCs homing to the infarcted myocardium thereby mediating cardiac remodeling post-MI. Mice were infarcted by coronary artery ligation and apelin-13 (1 mg/kg.d) was injected for three days prior to MI and for either 24 hours or 14 days post MI. Homing of vascular progenitor cell (CD133 + /c-kit + /Sca1 + , CD133 + /SDF-1α + and CD133 + /CXCR4 + ) into the ischemic area were examined at 24 hours and 14 days post-MI. Myocardial Akt, eNOS, VEGF, Jagged1, Notch3, SDF-1α and CXCR4 expression were assessed. Functional analyses were performed at day 14 after MI. Mice receiving apelin-13 treatment demonstrated upregulation of SDF-1α/CXCR4 expression and dramatically increased the number of CD133 + /c-kit + /Sca1 + , CD133 + /SDF-1α + and c-kit + /CXCR4 + cells in the infarcted hearts. Apelin-13 also significantly increased Akt and eNOS phosphorylation and upregulated VEGF, Jagged1, Notch3 expression in the ischemic hearts. This was accompanied by a significant reduction of myocardial apoptosis. Further, treatment with apelin-13 promoted myocardial angiogenesis, attenuated cardiac fibrosis and hypertrophy together with a significant improvement of cardiac function at 14 days post-MI mice. Apelin-13 increases angiogenesis and improves cardiac remodeling by a mechanism involving upregulation of SDF-1α/CXCR4 and homing of vascular progenitor cells.

Abstract 145: Apelin Reduces Myocardial Infarction Size and Promotes Angiogenesis by Increasing SDF-1/CXCR4 and AKT/eNOS/VEGF Pathways

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Lanfang Li ◽  
Heng Zeng ◽  
Jian-xiong Chen
Keyword(s):  
Myocardial Infarction ◽  
Myocardial Ischemia ◽  
Molecular Mechanisms ◽  
Myocardial Infarct ◽  
Ischemia Reperfusion ◽  
Border Zone ◽  
Heart Weight ◽  
Tunel Staining ◽  
Myocardial Infarct Size

Background: Apelin is an endogenous ligand for the angiotensin-like 1 receptor (APJ) and is emerging as a key player in the regulation of angiogenesis as well as ischemia/reperfusion injury. So far, little is known about the functional role of apelin in myocardial ischemia. We investigated the potential intracellular molecular mechanisms and protective role of apelin during myocardial ischemic injury. Methods and Results: Myocardial ischemia was achieved by ligation of the left anterior descending coronary artery (LAD) for 24 hours and 14 days. Myocardial apoptosis was detected by TUNEL staining. Akt, endothelial nitric oxide synthase (eNOS), vascular endothelial growth factor (VEGF), SDF-1 and CXCR4 expression were measured by western blot. The CD133+/cKit+/Sca1+, CD133/SDF-1+ and cKit/CXCR4+ cells were determined by immunostaining. Myocardial capillary and arteriole densities were analyzed in the border zone of infarcted myocardium at 14 d of ischemia. Treatment of C57BL/6J mice with apelin-13 (1 mg/Kg.d) by i.p. injection for 3 days before surgery results in significant decreases in TUNEL positive cells and myocardial infarct size at 24 hours of ischemia. Treatment with apelin increases the phosphorylation of AKT and eNOS and upregulates VEGF expression in the ischemic heart. Furthermore, treatment with apelin leads to the expression of SDF-1 and CXCR4 and increases in the number of CD133+/cKit+/Sca1+, CD133/SDF-1+ and cKit/CXCR4+ cells in ischemic hearts. Treatment with apelin also significantly increases myocardial capillary densities and arteriole formation together with a significant decrease in the ratio of heart weight to body weight at 14 days of ischemia. This is accompanied by a significant improvement of cardiac function after 14 days of ischemia. Conclusions: Our data demonstrate that apelin contributes to the protection of myocardial infarction and angiogenesis by the mechanisms involving in upregulation of SDF-1/CXCR4 and AKT/eNOS/VEGF pathways.

S6K inhibition renders cardiac protection against myocardial infarction through PDK1 phosphorylation of Akt

2011 ◽  
Vol 441 (1) ◽  
pp. 199-207 ◽  
Author(s):  
Ruomin Di ◽  
Xiangqi Wu ◽  
Zai Chang ◽  
Xia Zhao ◽  
Qiuting Feng ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Function ◽  
Weight Ratio ◽  
Left Ventricular ◽  
Cardiac Remodelling ◽  
Heart Weight ◽  
S6 Kinase ◽  
Beneficial Effects ◽  
Therapeutic Value ◽  
Specific Deletion

In the present study, we observed a rapid and robust activation of the ribosomal protein S6K (S6 kinase) provoked by MI (myocardial infarction) in mice. As activation of S6K promotes cell growth, we hypothesized that increased S6K activity contributes to pathological cardiac remodelling after MI and that suppression of S6K activation may prevent aberrant cardiac remodelling and improve cardiac function. In mice, administration of rapamycin effectively suppressed S6K activation in the heart and significantly improved cardiac function after MI. The heart weight/body weight ratio and fibrotic area were substantially reduced in rapamycin-treated mice. In rapamycin-treated mice, decreased cardiomyocyte remodelling and cell apoptosis were observed compared with vehicle-treated controls. Consistently, inhibition of S6K with PF-4708671 displayed similar protection against MI as rapamycin. Mechanistically, we observed significantly enhanced Thr308 phosphorylation and activation of Akt in rapamycin- and PF-4708671-treated hearts. Cardiomyocyte-specific deletion of PDK1 (phosphoinositide-dependent kinase 1) and Akt1/3 abolished cardioprotection after MI in the presence of rapamycin administration. These results demonstrate that S6K inhibition rendered beneficial effects on left ventricular function and alleviated adverse remodelling following MI in mice by enhancing Akt signalling, suggesting the therapeutic value of both rapamycin and PF-4708671 in treating patients following an MI.

scholarly journals Thymosin-β4 prevents cardiac rupture and improves cardiac function in mice with myocardial infarction

2014 ◽  
Vol 307 (5) ◽  
pp. H741-H751 ◽  
Author(s):  
Hongmei Peng ◽  
Jiang Xu ◽  
Xiao-Ping Yang ◽  
Xiangguo Dai ◽  
Edward L. Peterson ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Function ◽  
Cell Survival ◽  
Cardiac Remodeling ◽  
Cardiac Fibrosis ◽  
Capillary Density ◽  
Left Ventricular ◽  
Cardiac Rupture ◽  
Gelatinolytic Activity ◽  
P53 Expression

Thymosin-β4 (Tβ4) promotes cell survival, angiogenesis, and tissue regeneration and reduces inflammation. Cardiac rupture after myocardial infarction (MI) is mainly the consequence of excessive regional inflammation, whereas cardiac dysfunction after MI results from a massive cardiomyocyte loss and cardiac fibrosis. It is possible that Tβ4 reduces the incidence of cardiac rupture post-MI via anti-inflammatory actions and that it decreases adverse cardiac remodeling and improves cardiac function by promoting cardiac cell survival and cardiac repair. C57BL/6 mice were subjected to MI and treated with either vehicle or Tβ4 (1.6 mg·kg−1·day−1 ip via osmotic minipump) for 7 days or 5 wk. Mice were assessed for 1) cardiac remodeling and function by echocardiography; 2) inflammatory cell infiltration, capillary density, myocyte apoptosis, and interstitial collagen fraction histopathologically; 3) gelatinolytic activity by in situ zymography; and 4) expression of ICAM-1 and p53 by immunoblot analysis. Tβ4 reduced cardiac rupture that was associated with a decrease in the numbers of infiltrating inflammatory cells and apoptotic myocytes, a decrease in gelatinolytic activity and ICAM-1 and p53 expression, and an increase in the numbers of CD31-positive cells. Five-week treatment with Tβ4 ameliorated left ventricular dilation, improved cardiac function, markedly reduced interstitial collagen fraction, and increased capillary density. In a murine model of acute MI, Tβ4 not only decreased mortality rate as a result of cardiac rupture but also significantly improved cardiac function after MI. Thus, the use of Tβ4 could be explored as an alternative therapy in preventing cardiac rupture and restoring cardiac function in patients with MI.

scholarly journals Protection of Sacubitril/Valsartan against Pathological Cardiac Remodeling by Inhibiting the NLRP3 Inflammasome after Relief of Pressure Overload in Mice

2020 ◽  
Vol 34 (5) ◽  
pp. 629-640
Author(s):  
Xueling Li ◽  
Qin Zhu ◽  
Qingcheng Wang ◽  
Qinggang Zhang ◽  
Yaru Zheng ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Cardiac Remodeling ◽  
Cardiac Fibrosis ◽  
Pressure Overload ◽  
Myocardial Cell ◽  
Heart Weight ◽  
Inflammasome Activation ◽  
Clinical Prognosis ◽  
Nlrp3 Inflammasome Activation ◽  
Neprilysin Inhibitor

Abstract Background/aims The persistent existence of pathological cardiac remodeling, resulting from aortic stenosis, is related to poor clinical prognosis after successful transcatheter aortic valve replacement (TAVR). Sacubitril/valsartan (Sac/Val), comprising an angiotensin receptor blocker and a neprilysin inhibitor, has been demonstrated to have a beneficial effect against pathological cardiac remodeling, including cardiac fibrosis and inflammation in heart failure. The aim of this study was to determine whether Sac/Val exerts a cardioprotective effect after pressure unloading in mice. Methods and results Male C57BL/6 J mice were subjected to debanding (DB) surgery after 8 weeks (wk) of aortic banding (AB). Cardiac function was assessed by echocardiography, which indicated a protective effect of Sac/Val after DB. After treatment with Sac/Val post DB, decreased heart weight and myocardial cell size were observed in mouse hearts. In addition, histological analysis, immunofluorescence, and western blot results showed that Sac/Val attenuated cardiac fibrosis and inflammation after DB. Finally, our data indicated that Sac/Val treatment could significantly suppress NF-κB signaling and NLRP3 inflammasome activation in mice after relief of pressure overload. Conclusion Sac/Val exerted its beneficial effects to prevent maladaptive cardiac fibrosis and dysfunction in mice following pressure unloading, which was at least partly due to the inhibition of NLRP3 inflammasome activation.

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