Guanylyl cyclase‐A phosphorylation decreases cardiac hypertrophy and improves systolic function in male, but not female, mice

2021 ◽  
Vol 36 (1) ◽  
Author(s):  
Brandon M. Wagner ◽  
Jerid W. Robinson ◽  
Chastity L. Healy ◽  
Madeline Gauthier ◽  
Deborah M. Dickey ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Guanylyl Cyclase ◽  
Systolic Function ◽  
Female Mice

miRNA-143-3p-Sox6-Myh7 Pathway is Altered in Obesogenic Diet-Induced Cardiac Hypertrophy in Female Mice

2021 ◽  
Author(s):  
Tábatha de Oliveira Silva ◽  
Caroline Lino ◽  
Juliane Miranda ◽  
Camila Balbino-Silva ◽  
Guilherme Lunardon ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Female Mice ◽  
Obesogenic Diet

Abstract 282: Role of a Disintegrin and Metalloproteinase 15 in Cardiac Hypertrophy and Fibrosis Following Pressure Overload

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Priya Aujla ◽  
Sayantan Jana ◽  
Michael Chute ◽  
Zamaneh Kassiri
Keyword(s):  
Cardiac Hypertrophy ◽  
Cardiac Fibrosis ◽  
Cell Function ◽  
Systolic Function ◽  
Mechanical Strain ◽  
Pressure Overload ◽  
Compensatory Hypertrophy ◽  
Hypertrophic Response ◽  
A Disintegrin And Metalloproteinase

Introduction: Disintegrin and metalloproteinases (ADAMs) are membrane-bound cell surface enzymes that are capable of both proteolytic functions (via the metalloproteinase domain) and adhesive functions (via the disintegrin domain), whereby they can influence cell function and extracellular matrix (ECM) remodelling in the heart. ADAM15 is unique among the ADAMs, as it is also capable of degrading ECM proteins. ADAM12 and ADAM17 have been reported to regulate cardiac hypertrophy, but the role of ADAM15 in cardiac hypertrophy is not known. This study investigates the role of ADAM15 in cardiac hypertrophy and fibrosis following pressure overload. Methods & Results: Genetically modified male ADAM15-deficient ( Adam15 -/- ) and wildtype (WT) mice were subjected to cardiac pressure overload by transverse aortic constriction (TAC). Cardiac function and structural remodelling were assessed using echocardiography at 2-, and 6-wks post-TAC. Hearts were excised at 2-, or 6-wks post-TAC. Adam15 -/- hearts presented greater hypertrophy and decreased cardiac systolic function at 6wks post-TAC, but no difference at 2wks post-TAC compared to WT-TAC mice. Adam15 -/- hearts also showed exacerbated fibrosis at 6wks post-TAC, but not at 2wks post-TAC, compared to WT. Mechanical strain (i.e. pressure overload) triggers two temporally activated pathways leading to an initial compensatory hypertrophy, which can culminate to decompensation and dilated cardiomyopathy. Consistent with the greater hypertrophy, phosphorylation of ERK1/2, JNK1/2/3, and GSK3β was increased in Adam15 -/- mice. The calcineurin-NFAT pathways can mediate pressure overload-induced hypertrophy, but we found that Adam15-deficiency did not impact this pathway. The mechanism responsible for this function of ADAM15 requires further investigation. Conclusion: This study reports a novel cardioprotective function for ADAM15 in pressure overload, where loss of ADAM15 promotes cardiac fibrosis and decompensated cardiac hypertrophy but does not alter the compensated hypertrophic response.

scholarly journals Maternal androgen excess induces cardiac hypertrophy and left ventricular dysfunction in female mice offspring

2019 ◽  
Vol 116 (3) ◽  
pp. 619-632 ◽  
Author(s):  
Maria Manti ◽  
Romina Fornes ◽  
Gianluigi Pironti ◽  
Sarah McCann Haworth ◽  
Zhuge Zhengbing ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Maternal Obesity ◽  
Polycystic Ovary ◽  
Female Offspring ◽  
Left Ventricular ◽  
Calcium Handling ◽  
Regulation Of Transcription ◽  
Continuous Exposure ◽  
Female Mice ◽  
Obesity In Mice

Abstract Aims Polycystic ovary syndrome (PCOS) is a common endocrinopathy that is suggested to increase the risk for cardiovascular disease. How PCOS may lead to adverse cardiac outcomes is unclear and here we hypothesized that prenatal exposure to dihydrotestosterone (DHT) and/or maternal obesity in mice induce adverse metabolic and cardiac programming in female offspring that resemble the reproductive features of the syndrome. Methods and results The maternal obese PCOS phenotype was induced in mice by chronic high-fat–high-sucrose consumption together with prenatal DHT exposure. The prenatally androgenized (PNA) female offspring displayed cardiac hypertrophy during adulthood, an outcome that was not accompanied by aberrant metabolic profile. The expression of key genes involved in cardiac hypertrophy was up-regulated in the PNA offspring, with limited or no impact of maternal obesity. Furthermore, the activity of NADPH oxidase, a major source of reactive oxygen species in the cardiovascular system, was down-regulated in the PNA offspring heart. We next explored for early transcriptional changes in the heart of newly born PNA offspring, which could account for the long-lasting changes observed in adulthood. Neonatal PNA hearts displayed an up-regulation of transcription factors involved in cardiac hypertrophic remodelling and of the calcium-handling gene, Slc8a2. Finally, to determine the specific role of androgens in cardiovascular function, female mice were continuously exposed to DHT from pre-puberty to adulthood, with or without the antiandrogen flutamide. Continuous exposure to DHT led to adverse left ventricular remodelling, and increased vasocontractile responses, while treatment with flutamide partly alleviated these effects. Conclusion Taken together, our results indicate that intrauterine androgen exposure programmes long-lasting heart remodelling in female mouse offspring that is linked to left ventricular hypertrophy and highlight the potential risk of developing cardiac dysfunction in daughters of mothers with PCOS.

scholarly journals Orai1 Channel Inhibition Preserves Left Ventricular Systolic Function and Normal Ca 2+ Handling After Pressure Overload

Circulation ◽  
2020 ◽  
Vol 141 (3) ◽  
pp. 199-216 ◽  
Author(s):  
Fiona Bartoli ◽  
Marc A. Bailey ◽  
Baptiste Rode ◽  
Philippe Mateo ◽  
Fabrice Antigny ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Systolic Function ◽  
Systolic Dysfunction ◽  
Pressure Overload ◽  
Left Ventricular Systolic Function ◽  
Left Ventricular ◽  
Specific Expression ◽  
Channel Inhibition

Background: Orai1 is a critical ion channel subunit, best recognized as a mediator of store-operated Ca 2+ entry (SOCE) in nonexcitable cells. SOCE has recently emerged as a key contributor of cardiac hypertrophy and heart failure but the relevance of Orai1 is still unclear. Methods: To test the role of these Orai1 channels in the cardiac pathophysiology, a transgenic mouse was generated with cardiomyocyte-specific expression of an ion pore-disruptive Orai1 R91W mutant (C-dnO1). Synthetic chemistry and channel screening strategies were used to develop 4-(2,5-dimethoxyphenyl)-N-[(pyridin-4-yl)methyl]aniline (hereafter referred to as JPIII), a small-molecule Orai1 channel inhibitor suitable for in vivo delivery. Results: Adult mice subjected to transverse aortic constriction (TAC) developed cardiac hypertrophy and reduced ventricular function associated with increased Orai1 expression and Orai1-dependent SOCE (assessed by Mn 2+ influx). C-dnO1 mice displayed normal cardiac electromechanical function and cellular excitation-contraction coupling despite reduced Orai1-dependent SOCE. Five weeks after TAC, C-dnO1 mice were protected from systolic dysfunction (assessed by preserved left ventricular fractional shortening and ejection fraction) even if increased cardiac mass and prohypertrophic markers induction were observed. This is correlated with a protection from TAC-induced cellular Ca 2+ signaling alterations (increased SOCE, decreased [Ca 2+ ] i transients amplitude and decay rate, lower SR Ca 2+ load and depressed cellular contractility) and SERCA2a downregulation in ventricular cardiomyocytes from C-dnO1 mice, associated with blunted Pyk2 signaling. There was also less fibrosis in heart sections from C-dnO1 mice after TAC. Moreover, 3 weeks treatment with JPIII following 5 weeks of TAC confirmed the translational relevance of an Orai1 inhibition strategy during hypertrophic insult. Conclusions: The findings suggest a key role of cardiac Orai1 channels and the potential for Orai1 channel inhibitors as inotropic therapies for maintaining contractility reserve after hypertrophic stress.

Prolonged TSH Receptor A Subunit Immunization of Female Mice Leads to a Long-Term Model of Graves' Disease, Tachycardia, and Cardiac Hypertrophy

Endocrinology ◽  
2015 ◽  
Vol 156 (4) ◽  
pp. 1577-1589 ◽  
Author(s):  
Hans-Peter Holthoff ◽  
Sylvia Goebel ◽  
Zhongmin Li ◽  
Julia Faßbender ◽  
Andreas Reimann ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Tsh Receptor ◽  
Graves Disease ◽  
Female Mice ◽  
Term Model ◽  
A Subunit

scholarly journals Guanylyl Cyclase-A Inhibits Angiotensin II Type 2 Receptor-Mediated Pro-Hypertrophic Signaling in the Heart

Endocrinology ◽  
2009 ◽  
Vol 150 (8) ◽  
pp. 3759-3765 ◽  
Author(s):  
Yuhao Li ◽  
Yoshihiko Saito ◽  
Koichiro Kuwahara ◽  
Xianglu Rong ◽  
Ichiro Kishimoto ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Cardiac Hypertrophy ◽  
Guanylyl Cyclase ◽  
Weight Ratio ◽  
Cross Sectional ◽  
Cardiac Phenotype ◽  
At1 Antagonist ◽  
Hypertrophic Signaling ◽  
Deficient Mice

Angiotensin II plays a key role in the development of cardiac hypertrophy. The contribution of the angiotensin II type 1 receptor (AT1) in angiotensin II-induced cardiac hypertrophy is well established, but the role of AT2 signaling remains controversial. Previously, we have shown that natriuretic peptide receptor/guanylyl cyclase-A (GCA) signaling protects the heart from hypertrophy at least in part by inhibiting AT1-mediated pro-hypertrophic signaling. Here, we investigated the role of AT2 in cardiac hypertrophy observed in mice lacking GCA. Real-time RT-PCR and immunoblotting approaches indicated that the cardiac AT2 gene was overexpressed in GCA-deficient mice. Mice lacking AT2 alone did not exhibit an abnormal cardiac phenotype. In contrast, GCA-deficiency-induced increases in heart to body weight ratio, cardiomyocyte cross-sectional area, and collagen accumulation as evidenced by van Gieson staining were attenuated when AT2 was absent. Furthermore, the up-regulated cardiac expression of hypertrophy-related genes in GCA-null animals was also suppressed. Pharmacological blockade of AT2 with PD123319 similarly attenuated cardiac hypertrophy in GCA-deficient mice. In addition, whereas the AT1 antagonist olmesartan attenuated cardiac hypertrophy in GCA-deficient mice, this treatment was without effect on cardiac hypertrophy in GCA/AT2-double null mice, notwithstanding its potent antihypertensive effect in these animals. These results suggest that the interplay of AT2 and AT1 may be important in the development of cardiac hypertrophy. Collectively, our findings support the assertion that GCA inhibits AT2-mediated pro-hypertrophic signaling in heart and offer new insights into endogenous cardioprotective mechanisms during disease pathogenesis.

Thyroid hormone-induced overexpression of functional ryanodine receptors in the rabbit heart

2000 ◽  
Vol 278 (5) ◽  
pp. H1429-H1438 ◽  
Author(s):  
M. Jiang ◽  
A. Xu ◽  
S. Tokmakejian ◽  
N. Narayanan
Keyword(s):  
Thyroid Hormone ◽  
Cardiac Hypertrophy ◽  
Systolic Function ◽  
Ryanodine Receptors ◽  
Ventricular Myocardium ◽  
Rabbit Heart ◽  
Major Protein ◽  
Release Channel ◽  
Thyroid State ◽  
State Dependent

Modifications in the Ca2+-uptake and -release functions of the sarcoplasmic reticulum (SR) may be a major component of the mechanisms underlying thyroid state-dependent alterations in heart rate, myocardial contractility, and metabolism. We investigated the influence of hyperthyroid state on the expression and functional properties of the ryanodine receptor (RyR), a major protein in the junctional SR (JSR), which mediates Ca2+ release to trigger muscle contraction. Experiments were performed using homogenates and JSR vesicles derived from ventricular myocardium of euthyroid and hyperthyroid rabbits. Hyperthyroidism, with attendant cardiac hypertrophy, was induced by the injection of l-thyroxine (200 μg/kg body wt) daily for 7 days. Western blotting analysis using cardiac RyR-specific antibody revealed a significant increase (>50%) in the relative amount of RyR in the hyperthyroid compared with euthyroid rabbits. Ca2+-dependent, high-affinity [3H]ryanodine binding was also significantly greater (∼40%) in JSR from hyperthyroid rabbits. The Ca2+sensitivity of [3H]ryanodine binding and the dissociation constant for [3H]ryanodine did not differ significantly between euthyroid and hyperthyroid hearts. Measurement of Ca2+-release rates from passively Ca2+-preloaded JSR vesicles and assessment of the effect of RyR-Ca2+-release channel (CRC) blockade on active Ca2+-uptake rates revealed significantly enhanced (>2-fold) CRC activity in the hyperthyroid, compared with euthyroid, JSR. These results demonstrate overexpression of functional RyR in thyroid hormone-induced cardiac hypertrophy. Relative abundance of RyR may be responsible, in part, for the changes in SR Ca2+ release, cytosolic Ca2+ transient, and cardiac systolic function associated with thyroid hormone-induced cardiac hypertrophy.

scholarly journals Role of CyPA in cardiac hypertrophy and remodeling

2019 ◽  
Vol 39 (12) ◽  
Author(s):  
Mengfei Cao ◽  
Wei Yuan ◽  
Meiling Peng ◽  
Ziqi Mao ◽  
Qianru Zhao ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Interstitial Fibrosis ◽  
Systolic Function ◽  
Cardiac Fibroblasts ◽  
Cardiomyocyte Hypertrophy ◽  
Pathological Cardiac Hypertrophy ◽  
Complex Process

Abstract Pathological cardiac hypertrophy is a complex process and eventually develops into heart failure, in which the heart responds to various intrinsic or external stress, involving increased interstitial fibrosis, cell death and cardiac dysfunction. Studies have shown that oxidative stress is an important mechanism for this maladaptation. Cyclophilin A (CyPA) is a member of the cyclophilin (CyPs) family. Many cells secrete CyPA to the outside of the cells in response to oxidative stress. CyPA from blood vessels and the heart itself participate in a variety of signaling pathways to regulate the production of reactive oxygen species (ROS) and mediate inflammation, promote cardiomyocyte hypertrophy and proliferation of cardiac fibroblasts, stimulate endothelial injury and vascular smooth muscle hyperplasia, and promote the dissolution of extracellular matrix (ECM) by activating matrix metalloproteinases (MMPs). The events triggered by CyPA cause a decline of diastolic and systolic function and finally lead to the occurrence of heart failure. This article aims to introduce the role and mechanism of CyPA in cardiac hypertrophy and remodeling, and highlights its potential role as a disease biomarker and therapeutic target.

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