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.

scholarly journals GRK5 Controls SAP97-Dependent Cardiotoxic β 1 Adrenergic Receptor-CaMKII Signaling in Heart Failure

2020 ◽  
Vol 127 (6) ◽  
pp. 796-810
Author(s):  
Bing Xu ◽  
Minghui Li ◽  
Ying Wang ◽  
Meimi Zhao ◽  
Stefano Morotti ◽  
...  
Keyword(s):  
Heart Failure ◽  
Adrenergic Receptor ◽  
Critical Role ◽  
Pressure Overload ◽  
Adrenergic Stimulation ◽  
Critical Feature ◽  
Signaling Complex ◽  
Protein Receptor ◽  
C Terminus ◽  
Specific Deletion

Rationale: Cardiotoxic β 1 adrenergic receptor (β 1 AR)-CaMKII (calmodulin-dependent kinase II) signaling is a major and critical feature associated with development of heart failure. SAP97 (synapse-associated protein 97) is a multifunctional scaffold protein that binds directly to the C-terminus of β 1 AR and organizes a receptor signalosome. Objective: We aim to elucidate the dynamics of β 1 AR-SAP97 signalosome and its potential role in chronic cardiotoxic β 1 AR-CaMKII signaling that contributes to development of heart failure. Methods and Results: The integrity of cardiac β 1 AR-SAP97 complex was examined in heart failure. Cardiac-specific deletion of SAP97 was developed to examine β 1 AR signaling in aging mice, after chronic adrenergic stimulation, and in pressure overload hypertrophic heart failure. We show that the β 1 AR-SAP97 signaling complex is reduced in heart failure. Cardiac-specific deletion of SAP97 yields an aging-dependent cardiomyopathy and exacerbates cardiac dysfunction induced by chronic adrenergic stimulation and pressure overload, which are associated with elevated CaMKII activity. Loss of SAP97 promotes PKA (protein kinase A)-dependent association of β 1 AR with arrestin2 and CaMKII and turns on an Epac (exchange protein directly activated by cAMP)-dependent activation of CaMKII, which drives detrimental functional and structural remodeling in myocardium. Moreover, we have identified that GRK5 (G-protein receptor kinase-5) is necessary to promote agonist-induced dissociation of SAP97 from β 1 AR. Cardiac deletion of GRK5 prevents adrenergic-induced dissociation of β 1 AR-SAP97 complex and increases in CaMKII activity in hearts. Conclusions: These data reveal a critical role of SAP97 in maintaining the integrity of cardiac β 1 AR signaling and a detrimental cardiac GRK5-CaMKII axis that can be potentially targeted in heart failure therapy. Graphical Abstract: A graphical abstract is available for this article.

scholarly journals Oxidative Stress as A Mechanism for Functional Alterations in Cardiac Hypertrophy and Heart Failure

Antioxidants ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 931
Author(s):  
Anureet K. Shah ◽  
Sukhwinder K. Bhullar ◽  
Vijayan Elimban ◽  
Naranjan S. Dhalla
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Angiotensin Ii ◽  
Cardiac Hypertrophy ◽  
Cardiac Remodeling ◽  
Cardiac Dysfunction ◽  
Critical Role ◽  
Pressure Overload ◽  
Hypertrophied Heart ◽  
Vasoactive Hormones

Although heart failure due to a wide variety of pathological stimuli including myocardial infarction, pressure overload and volume overload is associated with cardiac hypertrophy, the exact reasons for the transition of cardiac hypertrophy to heart failure are not well defined. Since circulating levels of several vasoactive hormones including catecholamines, angiotensin II, and endothelins are elevated under pathological conditions, it has been suggested that these vasoactive hormones may be involved in the development of both cardiac hypertrophy and heart failure. At initial stages of pathological stimuli, these hormones induce an increase in ventricular wall tension by acting through their respective receptor-mediated signal transduction systems and result in the development of cardiac hypertrophy. Some oxyradicals formed at initial stages are also involved in the redox-dependent activation of the hypertrophic process but these are rapidly removed by increased content of antioxidants in hypertrophied heart. In fact, cardiac hypertrophy is considered to be an adaptive process as it exhibits either normal or augmented cardiac function for maintaining cardiovascular homeostasis. However, exposure of a hypertrophied heart to elevated levels of circulating hormones due to pathological stimuli over a prolonged period results in cardiac dysfunction and development of heart failure involving a complex set of mechanisms. It has been demonstrated that different cardiovascular abnormalities such as functional hypoxia, metabolic derangements, uncoupling of mitochondrial electron transport, and inflammation produce oxidative stress in the hypertrophied failing hearts. In addition, oxidation of catecholamines by monoamine oxidase as well as NADPH oxidase activation by angiotensin II and endothelin promote the generation of oxidative stress during the prolonged period by these pathological stimuli. It is noteworthy that oxidative stress is known to activate metallomatrix proteases and degrade the extracellular matrix proteins for the induction of cardiac remodeling and heart dysfunction. Furthermore, oxidative stress has been shown to induce subcellular remodeling and Ca2+-handling abnormalities as well as loss of cardiomyocytes due to the development of apoptosis, necrosis, and fibrosis. These observations support the view that a low amount of oxyradical formation for a brief period may activate redox-sensitive mechanisms, which are associated with the development of cardiac hypertrophy. On the other hand, high levels of oxyradicals over a prolonged period may induce oxidative stress and cause Ca2+-handling defects as well as protease activation and thus play a critical role in the development of adverse cardiac remodeling and cardiac dysfunction as well as progression of heart failure.

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 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.

scholarly journals Myocardial BDNF regulates cardiac bioenergetics through the transcription factor Yin Yang 1

2021 ◽  
Author(s):  
Xue Yang ◽  
Manling Zhang ◽  
Raymond J. Zimmerman ◽  
Qin Wang ◽  
An-chi Wei ◽  
...  
Keyword(s):  
Heart Failure ◽  
Transcription Factor ◽  
Critical Role ◽  
Mitochondrial Protein ◽  
Cardiac Response ◽  
Mouse Heart ◽  
Bdnf Expression ◽  
Yin Yang 1 ◽  
Mitochondrial Dna Copy Number ◽  
Yin Yang

ABSTRACTSerum Brain-derived Neurotrophic Factor (BDNF) is markedly decreased in heart failure patients. Both BDNF and its receptor, Tropomyosin Related Kinase Receptor (TrkB), are expressed in cardiomyocytes, however the role of myocardial BDNF signaling in cardiac pathophysiology is poorly understood. We found that myocardial BDNF expression was increased in mice with swimming exercise, but decreased in a mouse heart failure model. Cardiac-specific TrkB knockout (cTrkB KO) mice displayed a blunted adaptive cardiac response to exercise, with attenuated upregulation of transcription factor networks controlling mitochondrial biogenesis/metabolism, including Peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α). In response to pathological stress (transaortic constriction, TAC), cTrkB KO mice showed an exacerbated heart failure progression. The expression of PGC-1α and other metabolic transcription factors were downregulated in cTrkB KO mice exposed to TAC. Consistent with this, mitochondrial DNA copy number and mitochondrial protein abundance was markedly decreased in cTrkB KO mice, resulting in decreased mitochondrial respiratory function. We further unraveled that BDNF induces PGC-1α upregulation and bioenergetics through a novel signaling pathway, the pleiotropic transcription factor Yin Yang 1 (YY1). Taken together, our findings suggest that myocardial BDNF plays a critical role in regulating cellular energetics in the cardiac stress response.

Abstract 305: Pressure Overload-Induced Myocardial Hypertrophy Causes an Electrical Remodeling of CLC-3 Chloride Channels in Mouse Heart

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Dayue D Duan ◽  
Ying Yu ◽  
Guanlei Wang ◽  
Lingyu L Ye ◽  
Yi-gang Li
Keyword(s):  
Heart Failure ◽  
Chloride Channels ◽  
Myocardial Hypertrophy ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Cell Swelling ◽  
Protective Mechanism ◽  
Electrical Remodeling ◽  
Mouse Heart ◽  
Constitutive Activation

Backgrand: Myocardial hypertrophy causes an increase in myocyte volume and constitutive activation of a volume-sensitive outwardly-rectifying anion channel (VSORAC). The underlying molecular mechanisms and function of VSORAC in the electrical remodeling during myocardial hypertrophy and heart failure remain undefined. We tested whether cardiac CLC-3 chloride channels play a role in the hypertrophy-induced electrophysiological remodeling. Methods and Results: The age-matched CLC-3 knockout (Clcn3-/-) mice and their wild-type (Clcn3+/+) littermates were subjected to minimally-invasive transverse aortic banding (MTAB). In 77% (44/57) left ventricular (LV) myocytes isolated from MTAB-Clcn3+/+ mice a large VSORAC current was activated under isotonic conditions. Hypotonic cell-swelling caused no changes in the VSORAC but hypertonic cell-shrinkage significantly inhibited it. This constitutively-activated VSORAC had an anion selectivity of I->Cl->Asp-, and was inhibited by tamoxifen, PKC activation and intracellular application of anti-CLC-3 antibody. In the age-matched MTAB-Clcn3-/- mice, a significantly smaller outwardly-rectifying current was present in only 38% (36/94, P<0.05 vs MTAB-Clcn3+/+) LV myocytes. This current was neither increased by hypotonic stress nor inhibited by tamoxifen, PKC or anti-CLC-3 antibody, indicating not a VSORAC or CLC-3 current. Expression of CLC-3 protein was significantly increased in the LV tissues of MTAB-Clcn3+/+ mice but not in Sham-Clcn3+/+ and MTAB-Clcn3-/- mice. Both surface and intracardiac electrophysiological recordings revealed more atrial or ventricular arrhythmias in MTAB-Clcn3-/- mice than in MTAB- and Sham-Clcn3+/+ mice. Conclusions: Pressure-overload-induced myocardial hypertrophy causes an upregulation of CLC-3 expression and constitutive activation of CLC-3 may serve as a novel protective mechanism against the electrical remodeling during myocardial hypertrophy and heart failure.

scholarly journals MitoQ regulates redox-related noncoding RNAs to preserve mitochondrial network integrity in pressure-overload heart failure

2020 ◽  
Vol 318 (3) ◽  
pp. H682-H695 ◽  
Author(s):  
Seulhee Kim ◽  
Jiajia Song ◽  
Patrick Ernst ◽  
Mary N. Latimer ◽  
Chae-Myeong Ha ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Sarcoplasmic Reticulum ◽  
Posttranscriptional Regulation ◽  
Noncoding Rnas ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Mouse Heart ◽  
Mitochondrial Network ◽  
Mitofusin 2

Evidence suggests that mitochondrial network integrity is impaired in cardiomyocytes from failing hearts. While oxidative stress has been implicated in heart failure (HF)-associated mitochondrial remodeling, the effect of mitochondrial-targeted antioxidants, such as mitoquinone (MitoQ), on the mitochondrial network in a model of HF (e.g., pressure overload) has not been demonstrated. Furthermore, the mechanism of this regulation is not completely understood with an emerging role for posttranscriptional regulation via long noncoding RNAs (lncRNAs). We hypothesized that MitoQ preserves mitochondrial fusion proteins (i.e., mitofusin), likely through redox-sensitive lncRNAs, leading to improved mitochondrial network integrity in failing hearts. To test this hypothesis, 8-wk-old C57BL/6J mice were subjected to ascending aortic constriction (AAC), which caused substantial left ventricular (LV) chamber remodeling and remarkable contractile dysfunction in 1 wk. Transmission electron microscopy and immunostaining revealed defective intermitochondrial and mitochondrial-sarcoplasmic reticulum ultrastructure in AAC mice compared with sham-operated animals, which was accompanied by elevated oxidative stress and suppressed mitofusin (i.e., Mfn1 and Mfn2) expression. MitoQ (1.36 mg·day−1·mouse−1, 7 consecutive days) significantly ameliorated LV dysfunction, attenuated Mfn2 downregulation, improved interorganellar contact, and increased metabolism-related gene expression. Moreover, our data revealed that MitoQ alleviated the dysregulation of an Mfn2-associated lncRNA (i.e., Plscr4). In summary, the present study supports a unique mechanism by which MitoQ improves myocardial intermitochondrial and mitochondrial-sarcoplasmic reticulum (SR) ultrastructural remodeling in HF by maintaining Mfn2 expression via regulation by an lncRNA. These findings underscore the important role of lncRNAs in the pathogenesis of HF and the potential of targeting them for effective HF treatment. NEW & NOTEWORTHY We have shown that MitoQ improves cardiac mitochondrial network integrity and mitochondrial-SR alignment in a pressure-overload mouse heart-failure model. This may be occurring partly through preventing the dysregulation of a redox-sensitive lncRNA-microRNA pair (i.e., Plscr4-miR-214) that results in an increase in mitofusin-2 expression.

scholarly journals Ablation of cardiac TIGAR preserves myocardial energetics and cardiac function in the pressure overload heart failure model

2019 ◽  
Vol 316 (6) ◽  
pp. H1366-H1377
Author(s):  
Yoshifumi Okawa ◽  
Atsushi Hoshino ◽  
Makoto Ariyoshi ◽  
Satoshi Kaimoto ◽  
Shuhei Tateishi ◽  
...  
Keyword(s):  
Heart Failure ◽  
Pressure Overload ◽  
Cardiac Metabolism ◽  
High Energy ◽  
Left Ventricular ◽  
Lv Function ◽  
Mouse Heart ◽  
High Energy Phosphates ◽  
Wild Type ◽  
Myocardial Energetics

Despite the advances in medical therapy, the morbidity and mortality of heart failure (HF) remain unacceptably high. HF results from reduced metabolism–contraction coupling efficiency, so the modulation of cardiac metabolism may be an effective strategy for therapeutic interventions. Tumor suppressor p53 (TP53) and its downstream target TP53-induced glycolysis and apoptosis regulator (TIGAR) are known to modulate cardiac metabolism and cell fate. To investigate TIGAR’s function in HF, we compared myocardial, metabolic, and functional outcomes between TIGAR knockout (TIGAR−/−) mice and wild-type (TIGAR+/+) mice subjected to chronic thoracic transverse aortic constriction (TAC), a pressure-overload HF model. In wild-type mice hearts, p53 and TIGAR increased markedly during HF development. Eight weeks after TAC surgery, the left ventricular (LV) dysfunction, fibrosis, oxidative damage, and myocyte apoptosis were significantly advanced in wild-type than in TIGAR−/− mouse heart. Further, myocardial high-energy phosphates in wild-type hearts were significantly decreased compared with those of TIGAR−/− mouse heart. Glucose oxidation and glycolysis rates were also reduced in isolated perfused wild-type hearts following TAC than those in TIGAR−/− hearts, which suggest that the upregulation of TIGAR in HF causes impaired myocardial energetics and function. The effects of TIGAR knockout on LV function were also replicated in tamoxifen (TAM)-inducible cardiac-specific TIGAR knockout mice ( TIGARflox/flox/Tg(Myh6-cre/Esr1) mice). The ablation of TIGAR during pressure-overload HF preserves myocardial function and energetics. Thus, cardiac TIGAR-targeted therapy to increase glucose metabolism will be a novel strategy for HF. NEW & NOTEWORTHY The present study is the first to demonstrate that TP53-induced glycolysis and apoptosis regulator (TIGAR) is upregulated in the myocardium during experimental heart failure (HF) in mice and that TIGAR knockout can preserve the heart function and myocardial energetics during HF. Reducing TIGAR to enhance myocardial glycolytic energy production is a promising therapeutic strategy for HF.

Diacylglycerol kinase-ε restores cardiac dysfunction under chronic pressure overload: a new specific regulator of Gαq signaling cascade

2008 ◽  
Vol 295 (1) ◽  
pp. H245-H255 ◽  
Author(s):  
Takeshi Niizeki ◽  
Yasuchika Takeishi ◽  
Tatsuro Kitahara ◽  
Takanori Arimoto ◽  
Mitsunori Ishino ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Cardiac Dysfunction ◽  
Transient Receptor Potential ◽  
Critical Role ◽  
Pressure Overload ◽  
Receptor Potential ◽  
Heart Weight ◽  
Gpcr Signaling ◽  
Phenylephrine Infusion

Gαq protein-coupled receptor (GPCR) signaling pathway, which includes diacylglycerol (DAG) and protein kinase C (PKC), plays a critical role in cardiac hypertrophy. DAG kinase (DGK) catalyzes DAG phosphorylation and controls cellular DAG levels, thus acting as a regulator of GPCR signaling. It has been reported that DGKε acts specifically on DAG produced by inositol cycling. In this study, we examined whether DGKε prevents cardiac hypertrophy and progression to heart failure under chronic pressure overload. We generated transgenic mice with cardiac-specific overexpression of DGKε (DGKε-TG) using an α-myosin heavy chain promoter. There were no differences in cardiac morphology and function between wild-type (WT) and DGKε-TG mice at the basal condition. Either continuous phenylephrine infusion or thoracic transverse aortic constriction (TAC) was performed in WT and DGKε-TG mice. Increases in heart weight after phenylephrine infusion and TAC were abolished in DGKε-TG mice compared with WT mice. Cardiac dysfunction after TAC was prevented in DGKε-TG mice, and the survival rate after TAC was higher in DGKε-TG mice than in WT mice. Phenylephrine- and TAC-induced DAG accumulation, the translocation of PKC isoforms, and the induction of fetal genes were blocked in DGKε-TG mouse hearts. The upregulation of transient receptor potential channel (TRPC)-6 expression after TAC was attenuated in DGKε-TG mice. In conclusion, these results demonstrate the first evidence that DGKε restores cardiac dysfunction and improves survival under chronic pressure overload by controlling cellular DAG levels and TRPC-6 expression. DGKε may be a novel therapeutic target to prevent cardiac hypertrophy and progression to heart failure.

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