scholarly journals Cardiac overexpression of Mammalian enabled (Mena) exacerbates heart failure in mice

2013 ◽  
Vol 305 (6) ◽  
pp. H875-H884 ◽  
Author(s):  
Stephen L. Belmonte ◽  
Rashmi Ram ◽  
Deanne M. Mickelsen ◽  
Frank B. Gertler ◽  
Burns C. Blaxall
Keyword(s):  
Heart Failure ◽  
Cardiac Myocyte ◽  
Cardiac Injury ◽  
Actin Dynamics ◽  
Cardiac Pathology ◽  
Cardiac Pathophysiology ◽  
Precise Role ◽  
Functional Deterioration ◽  
Fractional Shortening

Mammalian enabled (Mena) is a key regulator of cytoskeletal actin dynamics, which has been implicated in heart failure (HF). We have previously demonstrated that cardiac Mena deletion produced cardiac dysfunction with conduction abnormalities and hypertrophy. Moreover, elevated Mena expression correlates with HF in human and animal models, yet the precise role of Mena in cardiac pathophysiology is unclear. In these studies, we evaluated mice with cardiac myocyte-specific Mena overexpression (TTA/TgTetMena) comparable to that observed in cardiac pathology. We found that the hearts of TTA/TgTetMena mice were functionally and morphologically comparable to wild-type littermates, except for mildly increased heart mass in the transgenic mice. Interestingly, TTA/TgTetMena mice were particularly susceptible to cardiac injury, as these animals experienced pronounced decreases in ejection fraction and fractional shortening as well as heart dilatation and hypertrophy after transverse aortic constriction (TAC). By “turning off” Mena overexpression in TTA/TgTetMena mice either immediately prior to or immediately after TAC surgery, we discovered that normalizing Mena levels eliminated cardiac hypertrophy in TTA/TgTetMena animals but did not preclude post-TAC cardiac functional deterioration. These findings indicate that hearts with increased levels of Mena fare worse when subjected to cardiac injury and suggest that Mena contributes to HF pathophysiology.

scholarly journals Macrophages modulate cardiac function in lipotoxic cardiomyopathy

2012 ◽  
Vol 303 (11) ◽  
pp. H1366-H1373 ◽  
Author(s):  
Joel D. Schilling ◽  
Heather M. Machkovech ◽  
Alfred H. J. Kim ◽  
Reto Schwedwener ◽  
Jean E. Schaffer
Keyword(s):  
Heart Failure ◽  
Cardiac Function ◽  
Cardiac Myocyte ◽  
Cardiac Injury ◽  
Transgenic Mouse Model ◽  
Obesity And Diabetes ◽  
Increased Risk ◽  
Inflammatory Activation ◽  
Lipotoxic Cardiomyopathy

Diabetes is associated with myocardial lipid accumulation and an increased risk of heart failure. Although cardiac myocyte lipid overload is thought to contribute to the pathogenesis of cardiomyopathy in the setting of diabetes, the mechanism(s) through which this occurs is not well understood. Increasingly, inflammation has been recognized as a key pathogenic feature of lipid excess and diabetes. In this study, we sought to investigate the role of inflammatory activation in the pathogenesis of lipotoxic cardiomyopathy using the α-myosin heavy chain promoter-driven long-chain acylCoA synthetase 1 (MHC-ACS) transgenic mouse model. We found that several inflammatory cytokines were upregulated in the myocardium of MHC-ACS mice before the onset of cardiac dysfunction, and this was accompanied by macrophage infiltration. Depletion of macrophages with liposomal clodrolip reduced the cardiac inflammatory response and improved cardiac function. Thus, in this model of lipotoxic cardiac injury, early induction of inflammation and macrophage recruitment contribute to adverse cardiac remodeling. These findings have implications for our understanding of heart failure in the setting of obesity and diabetes.

Abstract 71: STAT3 Affects Myofibrillar Structure and Its Loss May Contribute to Heart Failure in Hypertension

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Fouad Zouein ◽  
Carlos Zgheib ◽  
John Fuseler ◽  
John E Hall ◽  
Mazen Kurdi ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Myocytes ◽  
Transcriptional Activity ◽  
Cardiac Myocyte ◽  
Early Stage ◽  
Systolic Dysfunction ◽  
Wild Type ◽  
Patients With Heart Failure ◽  
Protective Proteins ◽  
Fractional Shortening

How hypertension causes heart failure is not known. Since patients with heart failure have reduced cardiac STAT3 and STAT3 KO mice develop heart failure with age, we tested the hypothesis that reduced STAT3 transcriptional activity contributes at an early stage to remodeling that precedes heart failure in hypertension using SA mice with a STAT3 S727A mutation. SA and wild type (WT) mice received angiotensin (A) II (1000 ng/kg/min) or saline (S) for 17 days. Hearts of WT and SA mice had similar levels of STAT3-induced protective proteins Bcl-xL and SOD2, and unlike STAT3 KO mice, cardiac miR-199a levels were not increased in SA mice. AII increased systolic blood pressure measured by telemetry in SA (124 ± 1 to 167 ± 3) and WT (122 ± 3 to 162 ± 3) mice to the same extent. AII increased cardiac levels of cytokines (pg/μg protein) associated with heart failure in both WT and SA mice, but significantly less so (P<0.05) in SA mice; IL-6, 13.6 ± 1.4 vs. 9.1 ± 0.6; TGFβ, 56 ± 4 vs. 38 ± 3 and MCP1 35 ± 2 vs. 22 ± 2. Compared to WT mice, hearts of SA mice showed signs of developing systolic dysfunction with AII as seen by a significant (P<0.05) reduction in ejection fraction (63.7 ± 7.1 to 51.7 ± 6.9) and fractional shortening (34.3 ± 4.9 to 26.4 ± 4.3). AII caused fibrosis in the left ventricle of both WT and SA mice characterized by cardiac myocyte loss and increased % collagen: WT+S, 5.59 ± 0.34; WT+AII, 15.70 ± 1.87; SA+S, 6.70 ± 0.40; SA+AII, 16.50 ± 1.91. In WT+AII mice there was a nonsignificant trend towards a loss of myofibrillar content of cardiac myocytes, but an increase in the mass of the myofibrils (IOD/myofibrillar area). In contrast, cardiac myocytes of SA+AII mice had a significant (P<0.001) % loss in myofibrils (5.71 ± 0.28) compared to SA+S (0.75 ± 0.07), WT+S (0.80 ± 0.06) and WT+AII (1.54 ± 0.10) mice. In addition, the mass of the myofibrils in SA+AII mice (6.01 ± 0.07) was significantly less (P<0.001) than those of SA+S mice (6.46 ± 0.04), although greater than WT+S (4.85 ± 0.06) or WT+AII (5.27 ± 0.08) mice. Our findings reveal that STAT3 transcriptional activity is important for proper morphology of the myofibrils of cardiac myocytes. Loss of STAT3 activity may impair cardiac function in the hypertensive heart due to defective myofibrillar structure and remodeling that may lead to heart failure.

Abstract 285: High Throughput Profiling of Gsk3α Regulated Fibroblast Kinome Reveals Raf as a Mediator of Fibrosis in Failing Heart

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Prachi Umbarkar ◽  
Sultan Tousif ◽  
Anand P Singh ◽  
Joshua C Anderson ◽  
Qinkun Zhang ◽  
...  
Keyword(s):  
High Throughput ◽  
Glycogen Synthase ◽  
Cardiac Injury ◽  
Collagen Gel ◽  
Microarray Platform ◽  
Negative Regulator ◽  
Post Injury ◽  
Cardiac Pathophysiology

Background: Heart failure is the leading cause of mortality, morbidity, and healthcare expenditures worldwide. Numerous studies have implicated Glycogen Synthase Kinase-3 (GSK-3) as a promising therapeutic target for cardiovascular diseases. GSK-3 isoforms appear to play overlapping, unique, and even opposing functions in the heart. Recently our group has identified cardiac fibroblast (CF) GSK3β as a negative regulator of fibrotic remodeling in the ischemic heart. However, the role of CF-GSK3α in cardiac pathophysiology is unknown. Methods and Results: GSK3α was deleted specifically from cardiac fibroblasts or myofibroblasts with tamoxifen-inducible TCF21- or periostin- promoter-driven Cre recombinase. At 2 months of age, WT and KO mice were subjected to cardiac injury, and heart functions were monitored by serial echocardiography. Histological analysis and morphometric studies were performed at 8 weeks post-injury. In both settings, GSK3α deletion restricted fibrotic remodeling and improved cardiac function. To investigate underlying mechanisms, we examined the effect of GSK3α deletion on myofibroblast transformation and pro-fibrotic TGFβ1-SMAD3 signaling in vitro . WT and KO mouse embryonic fibroblasts (MEFs) were treated with TGFβ1. Indeed, a significant reduction in cell migration, collagen gel contraction, and α-SMA expression in TGFβ1 treated KO MEFs confirmed that GSK3α is required for myofibroblast transformation. Surprisingly, GSK3α deletion had no effect on SMAD3 activation, indicating the pro-fibrotic role of GSK3α is SMAD3 independent. At 4 weeks post-injury, total proteins were isolated from CFs of WT and KO animals, and kinome profiling was performed by utilizing PamStation®12 high throughput microarray platform. The upstream kinase analysis identified the downregulation of RAF family kinase activity in GSK3α-KO-CFs. Moreover, mapping of significantly altered kinases against literature annotated interactions generated ERK-centric networks. These findings are consistent with previous studies that implicated ERK in fibrotic diseases across multiple organs. Conclusion: CF-GSK3α plays a causal role in the cardiac pathophysiology that could be therapeutically targeted for future clinical applications.

scholarly journals Systemic and heart autonomous effects of sphingosine Δ4 desaturase deficiency in lipotoxic cardiac pathophysiology

2020 ◽  
Vol 13 (8) ◽  
pp. dmm043083
Author(s):  
Stanley M. Walls ◽  
Dale A. Chatfield ◽  
Karen Ocorr ◽  
Greg L. Harris ◽  
Rolf Bodmer
Keyword(s):  
Cardiac Function ◽  
Fat Body ◽  
Model Systems ◽  
Specific Expression ◽  
Cardiac Pathology ◽  
Cardiac Chamber ◽  
Spatial Regulation ◽  
Cardiac Pathophysiology ◽  
Cardiac Steatosis ◽  
Fractional Shortening

ABSTRACTLipotoxic cardiomyopathy (LCM) is characterized by cardiac steatosis, including the accumulation of fatty acids, triglycerides and ceramides. Model systems have shown the inhibition of ceramide biosynthesis to antagonize obesity and improve insulin sensitivity. Sphingosine Δ4 desaturase (encoded by ifc in Drosophila melanogaster) enzymatically converts dihydroceramide into ceramide. Here, we examine ifc mutants to study the effects of desaturase deficiency on cardiac function in Drosophila. Interestingly, ifc mutants exhibited classic hallmarks of LCM: cardiac chamber dilation, contractile defects and loss of fractional shortening. This outcome was phenocopied in global ifc RNAi-mediated knockdown flies. Surprisingly, cardiac-specific ifc knockdown flies exhibited cardiac chamber restriction with no contractile defects, suggesting heart autonomous and systemic roles for ifc activity in cardiac function. Next, we demonstrated that ifc mutants exhibit suppressed Sphingosine kinase 1 (Sk1) expression. Ectopic overexpression of Sk1 was sufficient to prevent cardiac chamber dilation and loss of fractional shortening in ifc mutants. Partial rescue was also observed with cardiac- and fat-body-specific Sk1 overexpression. Finally, we showed that cardiac-specific expression of Drosophila inhibitor of apoptosis (dIAP) also prevented cardiac dysfunction in ifc mutants, suggesting a role for caspase activity in the observed cardiac pathology. Collectively, we show that spatial regulation of sphingosine Δ4 desaturase activity differentially affects cardiac function in heart autonomous and systemic mechanisms through tissue interplay.

HSP60 in heart failure: abnormal distribution and role in cardiac myocyte apoptosis

2007 ◽  
Vol 293 (4) ◽  
pp. H2238-H2247 ◽  
Author(s):  
Li Lin ◽  
S. C. Kim ◽  
Yin Wang ◽  
S. Gupta ◽  
B. Davis ◽  
...  
Keyword(s):  
Heart Failure ◽  
Plasma Membrane ◽  
Cell Surface ◽  
Cardiac Myocyte ◽  
Cardiac Injury ◽  
Acute Injury ◽  
Tnf Α ◽  
Inflammatory State ◽  
Cardiac Myocyte Apoptosis ◽  
End Stage

Heat shock protein (HSP) 60 is a mitochondrial and cytosolic protein. Previously, we reported that HSP60 doubled in end-stage heart failure, even though levels of the protective HSP72 were unchanged. Furthermore, we observed that acute injury in adult cardiac myocytes resulted in movement of HSP60 to the plasma membrane. We hypothesized that the inflammatory state of heart failure would cause translocation of HSP60 to the plasma membrane and that this would provide a pathway for cardiac injury. Two models were used to test this hypothesis: 1) a rat model of heart failure and 2) human explanted failing hearts. We found that HSP60 localized to the plasma membrane and was also found in the plasma early in heart failure. Plasma membrane HSP60 localized to lipid rafts and was detectable on the cell surface with the use of both flow cytometry and confocal microscopy. Localization of HSP60 to the cell surface correlated with increased apoptosis. In heart failure, HSP60 is in the plasma membrane fraction, on the cell surface, and in the plasma. Membrane HSP60 correlated with increased apoptosis. Release of HSP60 may activate the innate immune system, promoting a proinflammatory state, including an increase in TNF-α. Thus abnormal trafficking of HSP60 to the cell surface may be an early trigger for myocyte loss and the progression of heart failure.

scholarly journals Role of Endothelin 1 in the Pathogenesis of Chronic Chagasic Heart Disease

2005 ◽  
Vol 73 (4) ◽  
pp. 2496-2503 ◽  
Author(s):  
Herbert B. Tanowitz ◽  
Huan Huang ◽  
Linda A. Jelicks ◽  
Madhulika Chandra ◽  
Maria L. Loredo ◽  
...  
Keyword(s):  
Cardiac Myocyte ◽  
Acute Infection ◽  
Left Ventricular ◽  
Internal Diameter ◽  
Resonance Imaging ◽  
Endothelin 1 ◽  
Chagasic Cardiomyopathy ◽  
Brazil Strain ◽  
Fractional Shortening

ABSTRACT On the basis of previous observations, endothelin 1 (ET-1) has been suggested as contributing to the pathogenesis of Chagasic cardiomyopathy. Therefore, ET-1flox/flox;α-MHC-Cre(+) mice in which the ET-1 gene was deleted from cardiac myocytes and ET-1flox/flox;Tie 2 Cre(+) mice in which the ET-1 gene was deleted from endothelial cells were infected with Trypanosoma cruzi. Genetic controls for these cell-specific ET-1 knockout mice were used. Ninety percentage of all mice survived acute infection with the Brazil strain and were evaluated 130 days postinfection. Inflammation and fibrosis were observed in all infected mice; however, fibrosis was reduced in ET-1flox/flox;α-MHC-Cre(+) mice. Cardiac magnetic resonance imaging revealed that infection resulted in a significant increase in right ventricular internal diameter (RVID) in all mice except ET-1flox/flox;α-MHC-Cre(+) mice; i.e., RVID was not changed in infected ET-1flox/flox;α-MHC-Cre(+) mice. Echocardiography of the left ventricle demonstrated increased left ventricular end-diastolic diameter, reduced fractional shortening, and decreased relative wall thickness in infected mice. However, the magnitude of the changes was significantly less in ET-1flox/flox;α-MHC-Cre(+) mice compared to other groups. These data provide further evidence of a role for ET-1, particularly cardiac myocyte-derived ET-1, in the pathogenesis of chronic Chagasic cardiomyopathy.

scholarly journals The Cell Surface Receptors Ror1/2 Control Cardiac Myofibroblast Differentiation

2021 ◽  
Author(s):  
Nicholas W. Chavkin ◽  
Soichi Sano ◽  
Ying Wang ◽  
Kosei Oshima ◽  
Hayato Ogawa ◽  
...  
Keyword(s):  
Heart Failure ◽  
Planar Cell Polarity ◽  
Cardiac Fibrosis ◽  
Cardiac Fibroblasts ◽  
Cardiac Injury ◽  
Pressure Overload ◽  
Orphan Receptor ◽  
Myofibroblast Differentiation ◽  
Cultured Fibroblasts

AbstractBackgroundA hallmark of heart failure is cardiac fibrosis, which results from the injury-induced differentiation response of resident fibroblasts to myofibroblasts that deposit extracellular matrix. During myofibroblast differentiation, fibroblasts progress through polarization stages of early pro-inflammation, intermediate proliferation, and late maturation, but the regulators of this progression are poorly understood. Planar cell polarity receptors, receptor tyrosine kinase like orphan receptor 1 and 2 (Ror1/2), can function to promote cell differentiation and transformation. In this study, we investigated the role of the Ror1/2 in a model of heart failure with emphasis on myofibroblast differentiation.Methods and ResultsThe role of Ror1/2 during cardiac myofibroblast differentiation was studied in cell culture models of primary murine cardiac fibroblast activation and in knockout mouse models that underwent transverse aortic constriction (TAC) surgery to induce cardiac injury by pressure overload. Expression of Ror1 and Ror2 were robustly and exclusively induced in fibroblasts in hearts after TAC surgery, and both were rapidly upregulated after early activation of primary murine cardiac fibroblasts in culture. Cultured fibroblasts isolated from Ror1/2-KO mice displayed a pro-inflammatory phenotype indicative of impaired myofibroblast differentiation. Although the combined ablation of Ror1/2 in mice did not result in a detectable baseline phenotype, TAC surgery led to the death of all mice by day 6 that was associated with myocardial hyper-inflammation and vascular leakage.ConclusionsTogether, these results show that Ror1/2 are essential for the progression of myofibroblast differentiation and for the adaptive remodeling of the heart in response to pressure overload.

scholarly journals The Cell Surface Receptors Ror1/2 Control Cardiac Myofibroblast Differentiation

2021 ◽  
Author(s):  
Nicholas W. Chavkin ◽  
Soichi Sano ◽  
Ying Wang ◽  
Kosei Oshima ◽  
Hayato Ogawa ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Fibrosis ◽  
Cardiac Injury ◽  
Pressure Overload ◽  
Orphan Receptor ◽  
Myofibroblast Differentiation ◽  
Transverse Aortic Constriction ◽  
Aortic Constriction ◽  
Cultured Fibroblasts

Background A hallmark of heart failure is cardiac fibrosis, which results from the injury‐induced differentiation response of resident fibroblasts to myofibroblasts that deposit extracellular matrix. During myofibroblast differentiation, fibroblasts progress through polarization stages of early proinflammation, intermediate proliferation, and late maturation, but the regulators of this progression are poorly understood. Planar cell polarity receptors, receptor tyrosine kinase–like orphan receptor 1 and 2 (Ror1/2), can function to promote cell differentiation and transformation. In this study, we investigated the role of the Ror1/2 in a model of heart failure with emphasis on myofibroblast differentiation. Methods and Results The role of Ror1/2 during cardiac myofibroblast differentiation was studied in cell culture models of primary murine cardiac fibroblast activation and in knockout mouse models that underwent transverse aortic constriction surgery to induce cardiac injury by pressure overload. Expression of Ror1 and Ror2 were robustly and exclusively induced in fibroblasts in hearts after transverse aortic constriction surgery, and both were rapidly upregulated after early activation of primary murine cardiac fibroblasts in culture. Cultured fibroblasts isolated from Ror1/2 knockout mice displayed a proinflammatory phenotype indicative of impaired myofibroblast differentiation. Although the combined ablation of Ror1/2 in mice did not result in a detectable baseline phenotype, transverse aortic constriction surgery led to the death of all mice by day 6 that was associated with myocardial hyperinflammation and vascular leakage. Conclusions Together, these results show that Ror1/2 are essential for the progression of myofibroblast differentiation and for the adaptive remodeling of the heart in response to pressure overload.

Abstract 38: Important Role of Adiponectin in Volume Overload Induced Heart Failure

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Lili Wang ◽  
Desiree Wanders ◽  
Gayani Nanayakkara ◽  
Rajesh Amin ◽  
Robert L Judd ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Myocyte ◽  
Ventricular Remodeling ◽  
Vena Cava ◽  
Volume Overload ◽  
Infrarenal Aorta ◽  
Protective Effects ◽  
Fistula Surgery ◽  
Myocyte Contractility

Adiponectin (ADP) has been reported to exert cardiac protective effects during ventricular remodeling following pressure overload and myocardial ischemia. However, the potential role of ADP in the volume overload induced heart failure has not been reported. In this study we examined the effect of ADP in cardiac myocyte contractile dysfunction following sustained volume overload. Rat model of volume overload induced heart failure was created by infrarenal aorta-vena cava (A-V) fistula. Some rats were administered with adenoviral ADP (Ad-ADP) at 2-, 6-, and 9-weeks following fistula surgery. Serum total ADP levels were measured at 3 days before, 5 weeks and 10 weeks after fistula surgery. Myocyte contractility and intracellular Ca2+ transients were evaluated at 10 weeks following fistula. Results indicated a progressive reduction of serum ADP levels. In ventricular myocytes isolated from 10-week fistula rats, protein expression of ADP, AdipoR1/R2 and T-cadherin were decreased, and AMPK phosphorylation was reduced. Consistent with these, myocytes exhibited significant depression in cell shortening and intracellular Ca2+ transient. In vivo overexpression of adenovirus-mediated ADP in fistula rats significantly increased ADP serum levels, and prevented the depression of myocyte contractile performance. Moreover, in vitro treatment with ADP significantly improved myocyte contractility and intracellular Ca2+ transient from 10-week fistula rats, but had no effect on myocyte performance in control and Ad-ADP animals. These results demonstrate a positive correlation of ADP reduction and ventricular remodeling induced by volume overload. Adiponectin plays a protective role in volume overload-induced heart failure.

Abstract 447: Essential Role of Stromal Interaction Molecule 1 in Heart Failure

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Vishal R Mali ◽  
Maha Ali ◽  
Samuel Haddox ◽  
Mohamed Trebak ◽  
Khalid Matrougui
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Er Stress ◽  
Vascular Reactivity ◽  
Heart Weight ◽  
Infarct Area ◽  
Permanent Occlusion ◽  
Stress Activation ◽  
Fractional Shortening

Background: Stromal interacting molecule 1 (STIM1) is a calcium sensor in the endoplasmic reticulum (ER). We previously reported that STIM1 plays opposing roles in vascular smooth muscle cells (SMC) vs. endothelial cell in the regulation of vascular reactivity. However, the role of SMC STIM1 in heart failure is yet to be determined. Methods and Results: We utilize control (C57/Bl6) and mice lacking STIM1 specifically in SMC (Stim1 SMC-/- ). We subjected all mice to left anterior descending coronary artery (LAD) permanent occlusion for 3 weeks. We performed echocardiography before the LAD ligation and 3 week after. In the end, we sacrificed mice and harvested the heart for biochemical and histology studies. The heart weight, collagen, and infarct area were significantly augmented in control mice subjected to LAD occlusion. The diastolic (Ejection fraction) and systolic functions (fractional shortening) were significantly compromised in control mice subjected to LAD occlusion. Interestingly, the cardiac hypertrophy, the collagen content, the infarct area, the ejection fraction, and the fraction shortening were protected in Stim1 SMC-/- mice subjected to LAD occlusion. The protective effect of STIM1 disruption in SMC involved the reduction in ER stress activation, the autophagy, and apoptosis mechanisms. Conclusion: Our results indicate that the disruption of STIM1 in SMC protects the heart against chronic ischemia through the inhibition of ER stress, autophagy, and apoptosis.

Sign in / Sign up

Export Citation Format

Share Document