Tenascin-C enhances fibrosis and hypertrophy during pressure overload in the mouse heart

2014 ◽  
Vol 62 (S 01) ◽  
Author(s):  
E. Dzilic ◽  
M. Kreibich ◽  
F. Nagel ◽  
D. Santer ◽  
P. Moser ◽  
...  
Keyword(s):  
Pressure Overload ◽  
Mouse Heart ◽  
Tenascin C

Abstract 47: GATA Factors Caught at a Crossroad of Gene Duplication with Functional Divergence

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Jop H van Berlo ◽  
Jeffery D Molkentin
Keyword(s):  
Heart Failure ◽  
Functional Divergence ◽  
Severe Heart Failure ◽  
Pressure Overload ◽  
Mouse Heart ◽  
Adult Heart ◽  
Functional Roles ◽  
Hypertrophic Response ◽  
Gata Factors ◽  
Cardiac Gene

Background Six individual members comprise the GATA family of Zn finger-containing transcription factors that play major roles in the hematopoietic system and many mesoderm and endoderm derived tissues. The adult heart expresses both GATA4 and GATA6. Here, we examined the overlapping and diverging functional roles of GATA4 and GATA6 in the adult heart, both at baseline and under stress. Results Pressure overload by transverse aortic constriction (TAC) caused a blunted hypertrophic response when GATA4 was deleted from the adult heart, with severe heart failure ensuing after 4 weeks. Similarly, deletion of GATA6 from the mouse heart showed a blunted hypertrophic response and heart failure. Next, we deleted 1 allele of GATA4 and 1 allele of GATA6 from the adult heart, also resulting in blunted hypertrophy and cardiac dysfunction. Deletion of all four alleles of GATA4 and 6 resulted in spontaneous heart failure and death by 3 months of age. These results suggested functional overlap or synergistic activation. To address this concept more directly we deleted GATA6 from the adult heart and overexpressed either GATA4 or GATA6 in a cardiac-specific manner. As expected, we were able to completely revert the phenotype to wild type when GATA6 was overexpressed in mice that had GATA6 genetically deleted. Surprisingly, overexpression of GATA4 was unable to rescue the absence of GATA6 and actually worsened cardiac function in response to pressure overload. Possible explanations for this functional divergence were suggested by an observed rarefaction in capillaries of the heart in absence of GATA4, but enhanced angiogenesis in absence of GATA6. Moreover, when we induced cardiac hypertrophy through MAPK activation, we observed a critical necessity for GATA4, while GATA6 was dispensable. Conclusion Although GATA4 and 6 may be functionally complementary for cardiac gene expression and hypertrophy, they evolved some specific roles in the heart, such as angiogenesis and stress activation. We are currently unraveling how GATA4 and 6 may differentially regulate genes.

Abstract 238: Loss of AKAP150 Promotes Pathological Remodeling and Heart Failure Propensity by Disrupting Calcium Homeostasis and Contractile Reserve

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Lei Li ◽  
Jing Li ◽  
Benjamin Drum ◽  
Yi Chen ◽  
Haifeng Yin ◽  
...  
Keyword(s):  
Heart Failure ◽  
Critical Role ◽  
Pressure Overload ◽  
Contractile Reserve ◽  
Mouse Heart ◽  
Adrenergic Stimulation ◽  
Anchoring Protein ◽  
Key Aspects ◽  
Myocyte Contractility ◽  
Pathological Remodeling

Impaired Ca 2+ cycling and myocyte contractility are a hallmark of heart failure triggered by pathological stress such as hemodynamic overload. The A-Kinase anchoring protein AKAP150 has been shown to coordinate key aspects of adrenergic regulation of Ca 2+ cycling and excitation-contraction in cardiomyocytes. However, the role of the AKAP150 signaling complexes in the pathogenesis of heart failure is largely unknown. Here we investigate how AKAP150 signaling complexes impact Ca 2+ cycling, myocyte contractility, and heart failure susceptibility following pathological stress. We detected a significant reduction of AKAP150 expression in the failing mouse heart induced by pressure overload. Importantly, cardiac-specific AKAP150 knockout mice were predisposed to develop dilated cardiomyopathy with severe cardiac dysfunction and fibrosis after pressure overload. Loss of AKAP150 also promoted pathological remodeling and heart failure progression following myocardial infarction. However, ablation of AKAP150 did not appear to affect chronic activation of calcineurin-NFAT signaling in cardiomyocytes or pressure overload- or agonist- induced cardiac hypertrophy. Immunoprecipitation studies showed that AKAP150 was associated with SERCA2, phospholamban, and ryanodine receptor-2, providing a targeted control of sarcoplasmic reticulum Ca 2+ regulatory proteins. Mechanistically, loss of AKAP150 led to impaired Ca 2+ cycling and reduced myocyte contractility reserve following adrenergic stimulation or pressure overload. These findings define a critical role for AKAP150 in maintaining Ca 2+ homeostasis and myocardial ionotropy following pathological stress, suggesting the AKAP150 signaling pathway may serve as a novel therapeutic target for heart failure.

Abstract P189: RhoA Functions as an Antihypertrophic Switch in the Mouse Heart

2011 ◽  
Vol 109 (suppl_1) ◽  
Author(s):  
Davy Vanhoutte ◽  
Jop Van Berlo ◽  
Allen J York ◽  
Yi Zheng ◽  
Jeffery D Molkentin
Keyword(s):  
Cardiac Hypertrophy ◽  
Pressure Overload ◽  
Small Gtpase ◽  
Mouse Heart ◽  
Activity Levels ◽  
Lung Weight ◽  
Pathological Cardiac Hypertrophy ◽  
Rhoa Protein

Background. Small GTPase RhoA has been previously implicated as an important signaling effector within the cardiomyocyte. However, recent studies have challenged the hypothesized role of RhoA as an effector of cardiac hypertrophy. Therefore, this study examined the in vivo role of RhoA in the development of pathological cardiac hypertrophy. Methods and results . Endogenous RhoA protein expression and activity levels (GTP-bound) in wild-type hearts were significantly increased after pressure overload induced by transverse aortic constriction (TAC). To investigate the necessity of RhoA within the adult heart, RhoA-LoxP-targeted (RhoA flx/flx ) mice were crossed with transgenic mice expressing Cre recombinase under the control of the endogenous cardiomyocyte-specific β-myosin heavy chain (β-MHC) promoter to generate RhoA βMHC-cre mice. Deletion of RhoA with β-MHC-Cre produced viable adults with > 85% loss of RhoA protein in the heart, without altering the basic architecture and function of the heart compared to control hearts, at both 2 and 8 months of age. However, subjecting RhoA βMHC-cre hearts to 2 weeks of TAC resulted in marked increase in cardiac hypertrophy (HW/BW (mg/g): 9.5 ± 0.3 for RhoA βMHC-cre versus 7.7 ± 0.4 for RhoA flx/flx ; and cardiomyocyte size (mm 2 ): 407 ± 21 for RhoA βMHC-cre versus 262 ± 8 for RhoA flx/flx ; n ≥ 8 per group; p<0.01) and a significantly increased fibrotic response. Moreover, RhoA βMHC-cre hearts transitioned more quickly into heart failure whereas control mice maintained proper cardiac function (fractional shortening (%): 23.3 ± 1.2 for RhoA βMHC-cre versus 29.3 ± 1.2 for RhoA flx/flx ; n ≥ 8 per group; p<0.01; 12 weeks after TAC). The latter was further associated with a significant increase in lung weight normalized to body weight and re-expression of the cardiac fetal gene program. In addition, these mice also displayed greater cardiac hypertrophy in response to 2 weeks of angiotensinII/phenylephrine infusion. Conclusion. These data identify RhoA as an antihypertrophic molecular switch in the mouse heart.

Tenascin-C promotes chronic pressure overload-induced cardiac dysfunction, hypertrophy and myocardial fibrosis

2018 ◽  
Vol 36 (4) ◽  
pp. 847-856 ◽  
Author(s):  
Bruno K. Podesser ◽  
Maximilian Kreibich ◽  
Elda Dzilic ◽  
David Santer ◽  
Lorenz Förster ◽  
...  
Keyword(s):  
Myocardial Fibrosis ◽  
Cardiac Dysfunction ◽  
Pressure Overload ◽  
Tenascin C

scholarly journals Meox1 accelerates myocardial hypertrophic decompensation through Gata4

2017 ◽  
Vol 114 (2) ◽  
pp. 300-311 ◽  
Author(s):  
Dan Lu ◽  
Jizheng Wang ◽  
Jing Li ◽  
Feifei Guan ◽  
Xu Zhang ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Pressure Overload ◽  
Digital Gene Expression ◽  
Familial Hypertrophic Cardiomyopathy ◽  
Mouse Heart ◽  
Activity Data ◽  
Aberrant Expression ◽  
Downstream Target ◽  
Pathological Hypertrophy ◽  
Entry Points

AbstractAimsPathological hypertrophy is the result of gene network regulation, which ultimately leads to adverse cardiac remodelling and heart failure (HF) and is accompanied by the reactivation of a ‘foetal gene programme’. The Mesenchyme homeobox 1 (Meox1) gene is one of the foetal programme genes. Meox1 may play a role in embryonic development, but its regulation of pathological hypertrophy is not known. Therefore, this study investigated the effect of Meox1 on pathological hypertrophy, including familial and pressure overload-induced hypertrophy, and its potential mechanism of action.Methods and resultsMeox1 expression was markedly down-regulated in the wild-type adult mouse heart with age, and expression was up-regulated in heart tissues from familial dilated cardiomyopathy (FDCM) mice of the cTnTR141W strain, familial hypertrophic cardiomyopathy (FHCM) mice of the cTnTR92Q strain, pressure overload-induced HF mice, and hypertrophic cardiomyopathy (HCM) patients. Echocardiography, histopathology, and hypertrophic molecular markers consistently demonstrated that Meox1 overexpression exacerbated the phenotypes in FHCM and in mice with thoracic aorta constriction (TAC), and that Meox1 knockdown improved the pathological changes. Gata4 was identified as a potential downstream target of Meox1 using digital gene expression (DGE) profiling, real-time PCR, and bioinformatics analysis. Promoter activity data and chromatin immunoprecipitation (ChIP) and Gata4 knockdown analyses indicated that Meox1 acted via activation of Gata4 transcription.ConclusionMeox1 accelerated decompensation via the downstream target Gata4, at least in part directly. Meox1 and other foetal programme genes form a highly interconnected network, which offers multiple therapeutic entry points to dampen the aberrant expression of foetal genes and pathological hypertrophy.

scholarly journals Myricetin Alleviates Pathological Cardiac Hypertrophy via TRAF6/TAK1/MAPK and Nrf2 Signaling Pathway

2019 ◽  
Vol 2019 ◽  
pp. 1-14 ◽  
Author(s):  
Hai-han Liao ◽  
Nan Zhang ◽  
Yan-yan Meng ◽  
Hong Feng ◽  
Jing-jing Yang ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Pressure Overload ◽  
Mapk Signaling ◽  
Neonatal Rat ◽  
Mouse Heart ◽  
Pathological Cardiac Hypertrophy ◽  
Pathological Hypertrophy ◽  
Nrf2 Signaling Pathway

Myricetin (Myr) is a common plant-derived polyphenol and is well recognized for its multiple activities including antioxidant, anti-inflammation, anticancer, and antidiabetes. Our previous studies indicated that Myr protected mouse heart from lipopolysaccharide and streptozocin-induced injuries. However, it remained to be unclear whether Myr could prevent mouse heart from pressure overload-induced pathological hypertrophy. Wild type (WT) and cardiac Nrf2 knockdown (Nrf2-KD) mice were subjected to aortic banding (AB) surgery and then administered with Myr (200 mg/kg/d) for 6 weeks. Myr significantly alleviated AB-induced cardiac hypertrophy, fibrosis, and cardiac dysfunction in both WT and Nrf2-KD mice. Myr also inhibited phenylephrine- (PE-) induced neonatal rat cardiomyocyte (NRCM) hypertrophy and hypertrophic markers’ expression in vitro. Mechanically, Myr markedly increased Nrf2 activity, decreased NF-κB activity, and inhibited TAK1/p38/JNK1/2 MAPK signaling in WT mouse hearts. We further demonstrated that Myr could inhibit TAK1/p38/JNK1/2 signaling via inhibiting Traf6 ubiquitination and its interaction with TAK1 after Nrf2 knockdown in NRCM. These results strongly suggested that Myr could attenuate pressure overload-induced pathological hypertrophy in vivo and PE-induced NRCM hypertrophy via enhancing Nrf2 activity and inhibiting TAK1/P38/JNK1/2 phosphorylation by regulating Traf6 ubiquitination. Thus, Myr might be a potential strategy for therapy or adjuvant therapy for malignant cardiac hypertrophy.

scholarly journals 0303: Deleterious effects of Tenascin-C on cardiac remodeling induced by pressure overload involve microenvironment inflammation

2014 ◽  
Vol 6 ◽  
pp. 52
Author(s):  
Dounia Abbadi ◽  
Fanny Laroumanie ◽  
Anne-Catherine Prats ◽  
Angelo Parini ◽  
Nathalie Pizzinat
Keyword(s):  
Cardiac Remodeling ◽  
Pressure Overload ◽  
Tenascin C

Abstract P158: MicroRNA-22 Modulates Cardiac Gene Expression and Controls Compensation to Hemodynamic Stress in Mice

2011 ◽  
Vol 109 (suppl_1) ◽  
Author(s):  
Priyatansh Gurha ◽  
Robert Kelm ◽  
Mark Entman ◽  
George Taffet ◽  
Allan Bradley ◽  
...  
Keyword(s):  
Gene Expression ◽  
Critical Role ◽  
Cardiac Contractility ◽  
Pressure Overload ◽  
Mouse Heart ◽  
Primary Role ◽  
Translational Repressor ◽  
Muscle Gene Expression ◽  
Hemodynamic Stress

Recent evidence suggests that miRNAs play an important role in cardiac morphogenesis and pathophyiology of heart failure. To explore the role of miR-22 in the mouse heart physiology, we generated miR-22 null (KO) mice. Although, miR-22 KO mice showed normal cardiac structure and function at baseline, these mice are sensitized to maladaptive remodeling (cardiac dilation) and decompensation in response to pressure overload by transverse aortic constrictions (TAC) stimulation. Genome-wide molecular analysis of KO hearts revealed attenuated expression of numerous CarG-dependent genes encoding proteins that reside at the sarcomeric Z-disc (including Myh7, Acta1, Mlp, Melusin, MyoZ2) indicating that miR-22 is required for optimum muscle gene expression. Alterations in sarcomeric gene expression is especially interesting as this suggests a primary role of miR-22 in controlling cardiac contractility and adaptation to stress. Targetomics analysis revealed that mechanistically this effect could be modulated in part by miR-22 target PURB (Purine Rich element binding protein B), a transcriptional/translational repressor. In conclusion we define a critical role of miR-22 in cardiac adaptation to hemodynamic stress. Furthermore, these data provides a previously unseen essential molecular mechanism that underlies homeostatic control of sarcomeric protein expression in the heart.

Abstract 17904: Deficiency of Yes-associated Protein Promotes Cardiac Dysfunction in Response to Pressure Overload in the Mouse Heart

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Jaemin Byun ◽  
Dominic P Del Re ◽  
Peiyong Zhai ◽  
Akihiro Shirakabe ◽  
Junichi Sadoshima
Keyword(s):  
Cardiac Hypertrophy ◽  
Mammalian Cells ◽  
Diastolic Pressure ◽  
Systolic Function ◽  
Pressure Overload ◽  
Wall Stress ◽  
Left Ventricular ◽  
Lv Function ◽  
Mouse Heart ◽  
And Control

Yes-Associated Protein (YAP), a downstream effector of the Hippo pathway, plays an important role in regulating cell proliferation and survival in mammalian cells. We have shown that cardiac-specific loss of YAP leads to increased cardiomyocyte (CM) apoptosis and impaired hypertrophy during chronic myocardial infarction in the mouse heart. However, it remains unclear whether YAP mediates hypertrophy of individual CMs under stress conditions in vivo. We hypothesized that endogenous YAP plays an essential role in mediating hypertrophy and survival of CMs in response to pressure overload (PO). Three-month-old YAP+/fl;α-MHC-Cre (YAP-cKO) and YAP+/fl (control) mice were subjected to transverse aortic constriction (TAC). Two weeks later, YAP-cKO and control mice developed similar levels of cardiac hypertrophy (left ventricular (LV) weight/tibia length: 7.27±0.38, 6.93±0.29) compared to sham (5.08±0.14, 4.07±0.33). LV CM cross sectional area was similarly increased by TAC in YAP-cKO and control mice compared to their respective shams. Induction of fetal-type genes, such as Anf and Myh7, was also similar in YAP-cKO and control mice. YAP-cKO and control mice exhibited similar baseline LV systolic function (ejection fraction (EF): 75, 76%). YAP-cKO mice had significantly decreased LV function after TAC compared to Sham-control mice (EF: 51%, 76%, p<0.05) and TAC-control mice (75%, p<0.05). LV end diastolic pressure (LVEDP, mmHg) was significantly increased (19.3 ±3.2, 9.8±1.6, p<0.05), and LV +dP/dt (mmHg/s, 7250±588, 9500±453, p<0.01) and -dP/dt (mmHg/s, 6000±433, 7781± 314, p<0.05) were significantly decreased in YAP-cKO compared to in control mice after TAC. LV end diastolic diameter (mm) was significantly greater in YAP-cKO than in control mice after TAC (3.95±0.11, 3.35±0.15, p<0.05), whereas LV pressure was similar, suggesting that LV wall stress was elevated in YAP-cKO compared to in control mice. Since cardiac hypertrophy in YAP-cKO mice is similar to that in control mice despite elevated wall stress, the lack of YAP appears to limit the extent of cardiac hypertrophy in response to increased wall stress. These data suggest that endogenous YAP plays an important role in mediating adaptive hypertrophy and protecting the heart against PO.

Abstract 205: Differing Cardiac Phenotypes Between PP1α and PP1β Heart-Specific Gene-Deleted Mice

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Mannix Messier ◽  
Ruijie Liu ◽  
Jeffery Molkentin
Keyword(s):  
Weight Ratio ◽  
Pressure Overload ◽  
Cardiac Contraction ◽  
Calcium Handling ◽  
Heart Weight ◽  
Specific Gene ◽  
Mouse Heart ◽  
Major Protein ◽  
Intron 1 ◽  
Mammalian Tissues

Background: Protein phosphatase 1 is the major protein serine/threonine phosphatase in nearly all mammalian tissues, where it consists of three isoforms PP1α, PP1β, and PP1γ. However, the redundant or specific roles of each isoform in the heart is not known Methods: Each PP1 isoform was conditionally deleted in the mouse heart using a Cre-loxP approach. LoxP sites were introduced into intron 1 and 3 of each PP1α and PP1β. Both loxP-targeted lines were bred with mice expressing β-myosin heavy chain promoter driven Cre to achieve isoform specific gene deletion in the heart. Echocardiography was performed in these mice at different ages. We also investigated protein phosphorylation status of selected PP1 targets that underlie cardiac contraction and calcium handling from the hearts of these deleted mice. Results: Heart-specific deletion of PP1α caused a reduction of fractional shortening and worsening of cardiac function. Two weeks after transaortic constriction (TAC), PP1α deleted mice had greater increases in heart-weight to body-weight ratio compared with control mice, suggesting that PP1α was important for proper cardiac compensation. Interestingly, however, combined deletion of both PP1α and PP1β rescued the cardiac performance defects observed in PP1α deleted mice. Mechanistically, we found that deletion of PP1αβ led to increased phospholamban serine 16 and threonine 17 phosphorylation compared to that of PP1α. In conclusion, we showed that PP1 isoforms play distinct roles in the heart in regulating contractility and compensation after pressure overload stimulation.

Sign in / Sign up

Export Citation Format

Share Document