scholarly journals Adenosine regulation of microtubule dynamics in cardiac hypertrophy

2009 ◽  
Vol 297 (2) ◽  
pp. H523-H532 ◽  
Author(s):  
John T. Fassett ◽  
Xin Xu ◽  
Xinli Hu ◽  
Guangshuo Zhu ◽  
Joel French ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Knockout Mice ◽  
Cardiac Dysfunction ◽  
Pressure Overload ◽  
Colchicine Treatment ◽  
Microtubule Dynamics ◽  
Protective Effects ◽  
Wild Type ◽  
Extracellular Adenosine

There is evidence that endogenous extracellular adenosine reduces cardiac hypertrophy and heart failure in mice subjected to chronic pressure overload, but the mechanism by which adenosine exerts these protective effects is unknown. Here, we identified a novel role for adenosine in regulation of the cardiac microtubule cytoskeleton that may contribute to its beneficial effects in the overloaded heart. In neonatal cardiomyocytes, phenylephrine promoted hypertrophy and reorganization of the cytoskeleton, which included accumulation of sarcomeric proteins, microtubules, and desmin. Treatment with adenosine or the stable adenosine analog 2-chloroadenosine, which decreased hypertrophy, specifically reduced accumulation of microtubules. In hypertrophied cardiomyocytes, 2-chloroadenosine or adenosine treatment preferentially targeted stabilized microtubules (containing detyrosinated α-tubulin). Consistent with a role for endogenous adenosine in reducing microtubule stability, levels of detyrosinated microtubules were elevated in hearts of CD73 knockout mice (deficient in extracellular adenosine production) compared with wild-type mice (195%, P < 0.05). In response to aortic banding, microtubules increased in hearts of wild-type mice; this increase was exaggerated in CD73 knockout mice, with significantly greater amounts of tubulin partitioning into the cold-stable Triton-insoluble fractions. The levels of this stable cytoskeletal fraction of tubulin correlated strongly with the degree of heart failure. In agreement with a role for microtubule stabilization in promoting cardiac dysfunction, colchicine treatment of aortic-banded mice reduced hypertrophy and improved cardiac function compared with saline-treated controls. These results indicate that microtubules contribute to cardiac dysfunction and identify, for the first time, a role for adenosine in regulating cardiomyocyte microtubule dynamics.

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.

scholarly journals CXCR4 Cardiac Specific Knockout Mice Develop a Progressive Cardiomyopathy

2019 ◽  
Vol 20 (9) ◽  
pp. 2267 ◽  
Author(s):  
Thomas J. LaRocca ◽  
Perry Altman ◽  
Andrew A. Jarrah ◽  
Ron Gordon ◽  
Edward Wang ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Cardiac Myocytes ◽  
Knockout Mice ◽  
Cardiac Dysfunction ◽  
Left Ventricular ◽  
Subsequent Increase ◽  
Transition Electron Microscopy ◽  
Cardiac Phenotype

Activation of multiple pathways is associated with cardiac hypertrophy and heart failure. We previously published that CXCR4 negatively regulates β-adrenergic receptor (β-AR) signaling and ultimately limits β-adrenergic diastolic (Ca2+) accumulation in cardiac myocytes. In isolated adult rat cardiac myocytes; CXCL12 treatment prevented isoproterenol-induced hypertrophy and interrupted the calcineurin/NFAT pathway. Moreover; cardiac specific CXCR4 knockout mice show significant hypertrophy and develop cardiac dysfunction in response to chronic catecholamine exposure in an isoproterenol-induced (ISO) heart failure model. We set this study to determine the structural and functional consequences of CXCR4 myocardial knockout in the absence of exogenous stress. Cardiac phenotype and function were examined using (1) gated cardiac magnetic resonance imaging (MRI); (2) terminal cardiac catheterization with in vivo hemodynamics; (3) histological analysis of left ventricular (LV) cardiomyocyte dimension; fibrosis; and; (4) transition electron microscopy at 2-; 6- and 12-months of age to determine the regulatory role of CXCR4 in cardiomyopathy. Cardiomyocyte specific-CXCR4 knockout (CXCR4 cKO) mice demonstrate a progressive cardiac dysfunction leading to cardiac failure by 12-months of age. Histological assessments of CXCR4 cKO at 6-months of age revealed significant tissue fibrosis in knockout mice versus wild-type. The expression of atrial naturietic factor (ANF); a marker of cardiac hypertrophy; was also increased with a subsequent increase in gross heart weights. Furthermore, there were derangements in both the number and the size of the mitochondria within CXCR4 cKO hearts. Moreover, CXCR4 cKO mice were more sensitive to catocholamines, their response to β-AR agonist challenge via acute isoproterenol (ISO) infusion demonstrated a greater increase in ejection fraction, dp/dtmax, and contractility index. Interestingly, prior to ISO infusion, there were significant differences in baseline hemodynamics between the CXCR4 cKO compared to littermate controls. However, upon administering ISO, the CXCR4 cKO responded in a robust manner overcoming the baseline hemodynamic deficits reaching WT values supporting our previous data that CXCR4 negatively regulates β-AR signaling. This further supports that, in the absence of the physiologic negative modulation, there is an overactivation of down-stream pathways, which contribute to the development and progression of contractile dysfunction. Our results demonstrated that CXCR4 plays a non-developmental role in regulating cardiac function and that CXCR4 cKO mice develop a progressive cardiomyopathy leading to clinical heart failure.

scholarly journals Qindan Capsule Attenuates Myocardial Hypertrophy and Fibrosis in Pressure Overload-Induced Mice Involving mTOR and TGF-β1/Smad Signaling Pathway Inhibition

2021 ◽  
Vol 2021 ◽  
pp. 1-11
Author(s):  
Wenwu Bai ◽  
Min Ren ◽  
Wen Cheng ◽  
Xiaoting Lu ◽  
Deshan Liu ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Pressure Overload ◽  
Collagen I ◽  
High Dose ◽  
Protective Effects ◽  
Ang Ii ◽  
Stress Injury ◽  
Protein Levels ◽  
Tgf Β1

Qindan capsule (QC), a traditional Chinese medicine compound, has been used to treat hypertension in the clinic for over 30 years. It is still not known about the effects of QC on pressure overload-induced cardiac remodeling. Hence, this study aims to investigate the effects of QC on pressure overload-induced cardiac hypertrophy, fibrosis, and heart failure in mice and to determine the possible mechanisms. Transverse aortic constriction (TAC) surgery was used to induce cardiac hypertrophy and heart failure in C57BL/6 mice. Mice were treated with QC or losartan for 8 weeks after TAC surgery. Cardiac function indexes were evaluated with transthoracic echocardiography. Cardiac pathology was detected using HE and Masson’s trichrome staining. Cardiomyocyte ultrastructure was detected using transmission electron microscopy. Hypertrophy-related fetal gene expression was investigated using real-time RT-PCR. The expression of 8-OHdG and the concentration of MDA and Ang-II were assessed by immunohistochemistry stain and ELISA assay, respectively. The total and phosphorylated protein levels of mTOR, p70S6K, 4EBP1, Smad2, and Smad3 and the expression of TGF-β1 and collagen I were measured using western blot. The results showed that low- and high-dose QC improved pressure overload-induced cardiac hypertrophy, fibrosis, and dysfunction. QC inhibited ANP, BNP, and β-MHC mRNA expression in failing hearts. QC improved myocardial ultrastructure after TAC surgery. Furthermore, QC downregulated the expression of 8-OHdG and the concentration of MDA, 15-F2t-IsoP, and Ang-II in heart tissues after TAC surgery. We also found that QC inhibited the phosphorylation of mTOR, p70S6K, and 4EBP1 and the expression of TGF-β1, p-Smad2, p-Smad3, and collagen I in pressure overload-induced failing hearts. These data indicate that QC has direct benefic effects on pressure overload-induced cardiac hypertrophy, fibrosis, and dysfunction. The protective effects of QC involve prevention of increased oxidative stress injury and Ang-II levels and inhibition of mTOR and TGF-β1/Smad pathways in failing hearts.

scholarly journals Distinct Phenotypes Induced by Different Degrees of Transverse Aortic Constriction in C57BL/6N Mice

2021 ◽  
Vol 8 ◽  
Author(s):  
Haiyan Deng ◽  
Lei-Lei Ma ◽  
Fei-Juan Kong ◽  
Zengyong Qiao
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Cardiac Dysfunction ◽  
Cardiac Fibrosis ◽  
Disease Model ◽  
Pressure Overload ◽  
Mouse Strains ◽  
Transverse Aortic Constriction ◽  
Aortic Constriction ◽  
The Difference

The transverse aortic constriction (TAC) model surgery is a widely used disease model to study pressure overload–induced cardiac hypertrophy and heart failure in mice. The severity of adverse cardiac remodeling of the TAC model is largely dependent on the degree of constriction around the aorta, and the phenotypes of TAC are also different in different mouse strains. Few studies focus on directly comparing phenotypes of the TAC model with different degrees of constriction around the aorta, and no study compares the difference in C57BL/6N mice. In the present study, C57BL/6N mice aged 10 weeks were subjected to sham, 25G TAC, 26G TAC, and 27G TAC surgery for 4 weeks. We then analyzed the different phenotypes induced by 25G TAC, 26G TAC, and 27G TAC in c57BL/6N mice in terms of pressure gradient, cardiac hypertrophy, cardiac function, heart failure situation, survival condition, and cardiac fibrosis. All C57BL/6N mice subjected to TAC surgery developed significantly hypertrophy. Mice subjected to 27G TAC had severe cardiac dysfunction, severe cardiac fibrosis, and exhibited characteristics of heart failure at 4 weeks post-TAC. Compared with 27G TAC mice, 26G TAC mice showed a much milder response in cardiac dysfunction and cardiac fibrosis compared to 27G TAC, and a very small fraction of the 26G TAC group exhibited characteristics of heart failure. There was no obvious cardiac dysfunction, cardiac fibrosis, and characteristics of heart failure observed in 25G TAC mice. Based on our results, we conclude that the 25G TAC, 26G TAC, and 27G TAC induced distinct phenotypes in C57BL/6N mice.

Abstract 59: Role of Follistatin 315 in Regulating Cardiac Hypertrophy in Physiology and Pathophysiology

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Zhaobin Xu ◽  
Alisa D Blazek ◽  
Eric Beck ◽  
Jenna Alloush ◽  
Jackie Li ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cell Surface ◽  
Cardiac Hypertrophy ◽  
Genetically Modified ◽  
Pressure Overload ◽  
Wild Type ◽  
Surface Binding ◽  
Post Surgery ◽  
Genetically Modified Mice

Heart failure is characterized by initial compensatory changes, including the myocyte hypertrophy, chamber dilation, and matrix remodeling, that proceed until progressive dysfunction produces end stage heart failure and mortality. Recently, the roles of secreted factors in the heart that could regulate pathological hypertrophy, including follistatin (FST) and related molecules, have been examined by various investigators. FST is a molecule that blocks secretion of follicle-stimulating hormone from the pituitary and regulates members of the transforming growth factor beta (TGF-β) family including myostatin. Here we tested the effects of a particular FST isoform, FST288, on heart function in mice. The gene encoding FST produces three isoforms that differ in biological activities and cell surface binding capabilities. The FST315 isoform contains all six exons, and proteolytic cleavage of the FST315 C-terminal tail results in production of FST303. The lack of exon 6, which codes for the acidic C-terminal tail of the putative full-length protein, results in FST288. The missing acidic C-terminal tail region found in soluble FST315 allows FST288 to bind cell surface heparin-sulfated proteoglycans, accounting for the differential actions of these FST isoforms. Since mice that are null for the FST gene die embryonically, we used genetically modified mice that express only the FST288 isoform to test the role of FST315 in adult heart. Examination of these animals suggests that the loss of FST315 expression has limited effects on the heart at the resting state. When these mice are subjected to pressure overload through transverse aortic constriction (TAC) surgery they appear to be resistant to the compensatory cardiac hypertrophy present in wild type mice by 4 weeks post surgery. Both cardiac structure (examined by histology) and function (as measured by echocardiography and pressure/volume loops) following TAC are improved in the genetically modified mice when compared to wild type mice. This response is likely due to modification of the myostatin signaling pathway, one of the major targets of FST315. Overall, our data illustrates that FST315 is an important contributor to the progression of pressure overload induced cardiac hypertrophy.

Abstract 424: Loss of Sirt2 Protects Against Pressure Overload- and Ischemic Reperfusion Injury-induced Cardiac Dysfunction

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Teruki Sato ◽  
Xiaoyan Yan ◽  
Hsiang-Chun Chang ◽  
Chen Chunlei ◽  
Jason S Shapiro ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Reperfusion Injury ◽  
Cardiac Dysfunction ◽  
Pressure Overload ◽  
Cardiac Response ◽  
Neonatal Rat ◽  
Ros Production ◽  
Wild Type ◽  
Stress Injury

Introduction: Sirtuins are NAD+ dependent deacetylases and critical regulators of energy metabolism and response to oxidative stress. Sirtuin2 (SIRT2) is a cytoplasmic member of the sirtuin family, and has been shown to regulate cellular iron homeostasis through deacetylation of nuclear factor erythroid-derived 2-related factor 2 (NRF2). However, whether SIRT2-NRF2 pathway is involved in the development of heart failure remains unknown. Methods and results: To investigate the functional role of SIRT2 in the response to cardiac stress, SIRT2 knockout (KO) mice and their littermate controls were subjected to pressure overload by transverse aortic constriction (TAC). SIRT2 KO had normal appearance and cardiovascular parameters at baseline. However, in response to TAC, Sirt2 -/- mice displayed resistance to the pathological hypertrophic response, whereas wild type (WT) mice developed cardiac hypertrophy and heart failure. In addition, SIRT2 KO mice displayed less cardiac damage after /reperfusion injury. SIRT2 knockdown in neonatal rat cardiomyocytes (NRCM) reduced reactive oxygen species (ROS) production and cell death after H2O2 treatment. Since cellular oxidative stress is one of major contributor of cardiac dysfunction caused by both I/R injury and pressure overload, we examined whether NRF2 is associated with SIRT2-mediated cardiac response to oxidative stress. Levels of NRF2 was upregulated in NRCM with SIRT2 knockdown and treated with H2O2 compared to wild type (WT) cells. Moreover, NRF2 is translocated into the nucleus and its anti-oxidant target proteins are upregulated in NRCM with SIRT2 knockdown. SIRT2 was also found to bind and deacetylate NRF2 directly as determined by co-immunoprecipitation studies. This led to a reduction of its nuclear translocation and transcriptional activity. Finally, knockdown of both SIRT2 and NRF2 diminished the effects of SIRT2 knockdown on ROS production and cellular damage. Conclusion: These results indicate that SIRT2 contributes to pressure overload and I/R injury induced heart impairment in mice, and promotes oxidative stress injury in cardiomyocytes via deacetylating NRF2 and altering its activity.

Pressure-overload hypertrophy is unabated in mice devoid of AT1A receptors

1998 ◽  
Vol 274 (3) ◽  
pp. H868-H873 ◽  
Author(s):  
Masayoshi Hamawaki ◽  
Thomas M. Coffman ◽  
Andrew Lashus ◽  
Masaaki Koide ◽  
Michael R. Zile ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Knockout Mice ◽  
Weight Ratio ◽  
Pressure Overload ◽  
Renin Angiotensin System ◽  
Left Ventricular ◽  
Wild Type ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Hypertrophic Response

Mechanisms controlling cardiac growth are under intense investigation. Among these, the renin-angiotensin system has received great interest. In the current study, we tested the hypothesis that the renin-angiotensin system was not an obligate factor in cardiac hypertrophy. We examined the left ventricular hypertrophic response to a pressure overload in mice devoid of the AT1A receptor, the putative major effector of the growth response of the renin-angiotensin system. Aortic banding produced similar transband gradients in wild-type and AT1A knockout mice. The left ventricular mass-to-body weight ratio increased from 3.44 ± 0.08 to 5.62 ± 0.25 in wild-type ascending aortic-banded mice. The response in the knockout mice was not different (from 2.97 ± 0.13 to 5.24 ± 0.37). We conclude that the magnitude of cardiac hypertrophy is not affected by the absence of the AT1A receptor and its signaling pathway and that this component of the renin-angiotensin system is not necessary in cardiac hypertrophy.

scholarly journals Baicalin Attenuates Cardiac Dysfunction and Myocardial Remodeling in a Chronic Pressure-Overload Mice Model

2017 ◽  
Vol 41 (3) ◽  
pp. 849-864 ◽  
Author(s):  
Yanqing Zhang ◽  
Pingping Liao ◽  
Meng’en Zhu ◽  
Wei Li ◽  
Dan Hu ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Cardiac Dysfunction ◽  
Cardiac Fibrosis ◽  
Ventricular Remodeling ◽  
Pressure Overload ◽  
Protective Effects ◽  
Mice Model ◽  
Ischaemic Injury

Background/Aims: Baicalin has been shown to be effective for various animal models of cardiovascular diseases, such as pulmonary hypertension, atherosclerosis and myocardial ischaemic injury. However, whether baicalin plays a role in cardiac hypertrophy remains unknown. Here we investigated the protective effects of baicalin on cardiac hypertrophy induced by pressure overload and explored the potential mechanisms involved. Methods: C57BL/6J-mice were treated with baicalin or vehicle following transverse aortic constriction or Sham surgery for up to 8 weeks, and at different time points, cardiac function and heart size measurement and histological and biochemical examination were performed. Results: Mice under pressure overload exhibited cardiac dysfunction, high mortality, myocardial hypertrophy, increased apoptosis and fibrosis markers, and suppressed cardiac expression of PPARα and PPARβ/δ. However, oral administration of baicalin improved cardiac dysfunction, decreased mortality, and attenuated histological and biochemical changes described above. These protective effects of baicalin were associated with reduced heart and cardiomyocyte size, lower fetal genes expression, attenuated cardiac fibrosis, lower expression of profibrotic markers, and decreased apoptosis signals in heart tissue. Moreover, we found that baicalin induced PPARα and PPARβ/δ expression in vivo and in vitro. Subsequent experiments demonstrated that long-term baicalin treatment presented no obvious cardiac lipotoxicity. Conclusions: The present results demonstrated that baicalin attenuates pressure overload induced cardiac dysfunction and ventricular remodeling, which would be due to suppressed cardiac hypertrophy, fibrosis, apoptosis and metabolic abnormality.

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.

NRSF-GNAO1-CaMK2 axis exacerbates cardiac remodeling and progresses heart failure by impairing Ca2+ homeostasis

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
H Inazumi ◽  
K Kuwahara ◽  
Y Kuwabara ◽  
Y Nakagawa ◽  
H Kinoshita ◽  
...  
Keyword(s):  
Heart Failure ◽  
Transgenic Mice ◽  
Knockout Mice ◽  
Cardiac Remodeling ◽  
Cardiac Dysfunction ◽  
Intracellular Signaling ◽  
Molecular Mechanisms ◽  
Systolic Function ◽  
Dominant Negative Mutant ◽  
Funding Source

Abstract Background In the development of heart failure, pathological intracellular signaling reactivates fetal cardiac genes, which leads to maladaptive remodeling and cardiac dysfunction. We previously reported that a transcriptional repressor, neuron restrictive silencer factor (NRSF) represses fetal cardiac genes and maintains normal cardiac function under normal conditions, while hypertrophic stimuli de-repress this NRSF mediated repression via activation of CaMKII. Molecular mechanisms by which NRSF maintains cardiac systolic function remains to be determined, however. Purpose To elucidate how NRSF maintains normal cardiac homeostasis and identify the novel therapeutic targets for heart failure. Methods and results We generated cardiac-specific NRSF knockout mice (NRSF cKO), and found that these NRSF cKO showed cardiac dysfunction and premature deaths accompanied with lethal arrhythmias, as was observed in our previously reported cardiac-specific dominant-negative mutant of NRSF transgenic mice (dnNRSF-Tg). By cDNA microarray analysis of dnNRSF-Tg and NRSF-cKO, we identified that expression of Gnao1 gene encoding Gαo, a member of inhibitory G proteins, was commonly increased in ventricles of both types of mice. ChIP-seq analysis, reporter assay and electrophoretic mobility shift assay identified that NRSF transcriptionally regulates Gnao1 gene expression. Genetic Knockdown of Gαo in dnNRSF-Tg and NRSF-cKO by crossing these mice with Gnao1 knockout mice ameliorated the reduced systolic function, increased arrhythmogenicity and reduced survival rates. Transgenic mice expressing a human GNAO1 in their hearts (GNAO1-Tg) showed progressive cardiac dysfunction with cardiac dilation. Ventricles obtained from GNAO1-Tg have increased phosphorylation level of CaMKII and increased expression level of endogenous mouse Gnao1 gene. These data suggest that increased cardiac expression of Gαo is sufficient to induce pathological Ca2+-dependent signaling and cardiac dysfunction, and that Gαo forms a positive regulatory circuit with CaMKII and NRSF. Electrophysiological analysis in ventricular myocytes of dnNRSF-Tg revealed that impaired Ca2+ handling via alterations in localized L-type calcium channel (LTCC) activities; decreased T-tubular and increased surface sarcolemmal LTCC activities, underlies Gαo-mediated cardiac dysfunction. Furthermore, we also identified increased expression of Gαo in ventricles of two different heart failure mice models, mice with transverse aortic constriction and mice carrying a mutant cardiac troponin T, and confirmed that genetic reduction of Gαo prevented the progression of cardiac dysfunction in both types of mice. Conclusions Increased expression of Gαo, induced by attenuation of NRSF-mediated repression forms a pathological circuit via activation of CaMKII. This circuit exacerbates cardiac remodeling and progresses heart failure by impairing Ca2+ homeostasis. Gαo is a potential therapeutic target for heart failure. Figure 1 Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Grants-in –Aid for Scientific Research from the Japan Society for the Promotion of Science

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