Ovariectomy exacerbates the hypertrophic response in a mouse model of primary cardiac hypertrophy

Background: Thymosin beta-4 (Tβ4) is a ubiquitous protein with many properties relating to cell proliferation and differentiation that promotes wound healing and modulates inflammatory mediators. However, the role of Tβ4 in cardiomyocytes hypertrophy is currently unknown. The purpose of this study is to dissect the cardio-protective mechanism of Tβ4 in Ang II induced cardiac hypertrophy. Methods: Rat neonatal cardiomyocytes with or without Tβ4 pretreatment were stimulated with Ang II and expression of cell sizes, hypertrophy marker genes and Wnt signaling components was evaluated by quantitative real-time PCR, western blotting and fluorescent microscopy. Selected target gene Wisp-1 was either overexpressed or silenced by siRNA transfections in neonatal cardiomyocytes and effect of Tβ4 in Ang II-induced cardiac hypertrophy was evaluated. Results: Pre-treatment of Tβ4 resulted in reduction of cell sizes, hypertrophy marker genes and WNT-associated gene expression and levels induced by Ang II in cardiomyocytes. Tβ4 pretreatment also resulted in an increase in the expression of antiapoptotic proteins and reduction of Bax/BCl 2 ratio in the cardiomyocytes. Wisp-1 overexpression promotes cardiac hypertrophy and was reversed by pretreatment with Tβ4. Knocking down of Wisp1 partly rescue the cells from hypertrophic response after Tβ4 treatment. Conclusion: This is the first report that demonstrates the effect of Tβ4 on cardiomyocytes hypertrophy and its capability to selectively target Wisp-1 in neonatal cardiomyocytes thus preventing cell death, thereby, protecting the myocardium. Wisp-1 promotes the cardiac hypertrophy which was prevented by Tβ4 treatment.

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Preserved heart function after left ventricular pressure overload in adult mice subjected to neonatal cardiac hypoplasia

Journal of Developmental Origins of Health and Disease ◽

10.1017/s2040174417000514 ◽

2017 ◽

Vol 9 (1) ◽

pp. 112-124

Author(s):

K. Heinecke ◽

A. Heuser ◽

F. Blaschke ◽

C. Jux ◽

L. Thierfelder ◽

...

Keyword(s):

Mouse Model ◽

Heart Function ◽

Pressure Overload ◽

Left Ventricular Pressure ◽

Cellular Level ◽

Left Ventricular ◽

P38 Map Kinase ◽

Cross Sectional ◽

Hypertrophic Response ◽

Cardiomyocyte Number

Intrauterine growth restriction in animal models reduces heart size and cardiomyocyte number at birth. Such incomplete cardiomyocyte endowment is believed to increase susceptibility toward cardiovascular disease in adulthood, a phenomenon referred to as developmental programming. We have previously described a mouse model of impaired myocardial development leading to a 25% reduction of cardiomyocyte number in neonates. This study investigated the response of these hypoplastic hearts to pressure overload in adulthood, applied by abdominal aortic constriction (AAC). Echocardiography revealed a similar hypertrophic response in hypoplastic hearts compared with controls over the first 2 weeks. Subsequently, control mice develop mild left ventricular (LV) dilation, wall thinning and contractile dysfunction 4 weeks after AAC, whereas hypoplastic hearts fully maintain LV dimensions, wall thickness and contractility. At the cellular level, controls exhibit increased cardiomyocyte cross-sectional area after 4 weeks pressure overload compared with sham operated animals, but this hypertrophic response is markedly attenuated in hypoplastic hearts. AAC mediated induction of fibrosis, apoptosis or cell cycle activity was not different between groups. Expression of fetal genes, indicative of pathological conditions, was similar in hypoplastic and control hearts after AAC. Among various signaling pathways involved in cardiac hypertrophy, pressure overload induces p38 MAP-kinase activity in hypoplastic hearts but not controls compared with the respective sham operated animals. In summary, based on the mouse model used in this study, our data indicates that adult hearts after neonatal cardiac hypoplasia show an altered growth response to pressure overload, eventually resulting in better functional outcome compared with controls.

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Accelerated Development of Pressure Overload–Induced Cardiac Hypertrophy and Dysfunction in an RyR2-R176Q Knockin Mouse Model

Hypertension ◽

10.1161/hypertensionaha.109.146449 ◽

2010 ◽

Vol 55 (4) ◽

pp. 932-938 ◽

Cited By ~ 47

Author(s):

Ralph J. van Oort ◽

Jonathan L. Respress ◽

Na Li ◽

Corey Reynolds ◽

Angela C. De Almeida ◽

...

Keyword(s):

Mouse Model ◽

Cardiac Hypertrophy ◽

Pressure Overload ◽

Knockin Mouse

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Letter to the Editor: “Increased Circulating FGF23 Does Not Lead to Cardiac Hypertrophy in the Male Hyp Mouse Model of XLH”

Endocrinology ◽

10.1210/en.2018-00690 ◽

2018 ◽

Vol 159 (11) ◽

pp. 3655-3656

Author(s):

Xiaobin Han ◽

L Darryl Quarles

Keyword(s):

Mouse Model ◽

Cardiac Hypertrophy ◽

Letter To The Editor

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Abstract 309: Small Heterodimer Partner Blocks Cardiac Hypertrophy By Interfering With GATA6 Signaling

Circulation Research ◽

10.1161/res.115.suppl_1.309 ◽

2014 ◽

Vol 115 (suppl_1) ◽

Author(s):

Yoon Seok Nam ◽

Duk-Hwa Kwon ◽

Gwang Hyeon Eom ◽

Hyun Kook

Keyword(s):

Cardiac Hypertrophy ◽

Heart Diseases ◽

Cardiomyocyte Hypertrophy ◽

Physical Interaction ◽

Orphan Nuclear Receptor ◽

Promoter Regions ◽

Adult Heart ◽

Hypertrophic Response ◽

Small Heterodimer Partner

Rationale: Small heterodimer partner (SHP; NR0B2) is an atypical orphan nuclear receptor that lacks a conventional DNA binding domain. By interacting with other transcription factors, SHP regulates diverse biological events including glucose metabolism in liver. The role of SHP in adult heart diseases has not yet been demonstrated. Objective: We aimed to investigate the role of SHP in adult heart in association with cardiac hypertrophy. Methods and Results: The roles of SHP in cardiac hypertrophy were tested in primary cultured cardiomyocytes and in animal models. SHP null mice showed a hypertrophic phenotype. Hypertrophic stresses repressed the expression of SHP, whereas forced expression of SHP blocked the development of cardiomyocyte hypertrophy. SHP reduced the protein amount of Gata6. By direct physical interaction with Gata6, SHP interfered with the binding of Gata6 to GATA binding elements in the promoter regions of natriuretic peptide precursor type A. Metformin, an anti-diabetic agent, induced SHP and suppressed cardiac hypertrophy. The metformin-induced anti-hypertrophic effect was attenuated either by SHP siRNA in cardiomyocytes or in SHP null mice. Conclusions: These results establish SHP as a novel anti-hypertrophic regulator that acts by interfering with GATA6 signaling. SHP may participate in the metformin-induced anti-hypertrophic response.

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Abstract 454: Protein Phosphatase Pp2a Regulates Hypertrophic Response Through Hdac2 Dephosphorylation in the Heart

Circulation Research ◽

10.1161/res.119.suppl_1.454 ◽

2016 ◽

Vol 119 (suppl_1) ◽

Author(s):

Hyun-Ki Min ◽

Somy Yoon ◽

Duk-Hwa Kwon ◽

Hyun Kook ◽

Gwang Hyeon Eom

Keyword(s):

Transgenic Mice ◽

Cardiac Hypertrophy ◽

Cardiac Remodeling ◽

Protein Phosphatase ◽

Wild Type ◽

Therapeutic Implications ◽

Hypertrophic Response ◽

Adaptive Process ◽

Binding Partners ◽

Do So

Rationale: Cardiac hypertrophy is an adaptive process to meet the hemodynamic demands from exogenous stresses, and histone deacetylase (HDAC) 2 plays central role in cardiac remodeling. Recently, we have suggested the importance of acetylation of HDAC2; however, specific phosphatase of HDAC2 remains unclear. Objective: We aimed to delineate the phosphatase of HDAC2 in the development of cardiac hypertrophy and to suggest therapeutic implications of those phosphatase in cardiac remodeling. Methods and Results: We performed complex-isolation assay in the heart and found that Hdac2 physically interacted with the Ppp2ca, and Hsp70. Ppp2ca kept Hdac2 unphosphorylated in the absence of hypertrophic stresses. Hypertrophic stresses-induced Hdac2 K75 acetylation, which then allowed Ppp2ca to dissociate from Hdac2, which led to phosphorylate Hdac2. The agonist-induced hypertrophy was significantly attenuated in transgenic mice heart expressing Ppp2ca. Forced expression of phosphorylation mimicking mutant of Hdac2, Hdac2 S394E, successfully overcame to antihypertrophic effects of Ppp2ca, whereas wild type of Hdac2 failed to do so. On the other hand, hypertrophic stresses induced Hsp70, one of the binding partners of Hdac2, which then preferentially bound to phosphorylated Hdac2 rather than to unphosphorylated one. The increase in expression of Hsp70 led to dissociate Ppp2ca from Hdac2. Hsp70 significantly increased phosphorylation of Hdac2 by protection from Ppp2ca. Cardiac hypertrophy was observed in the TgHsp70 mice and hyper-phosphorylation of Hdac2 was also detected. Double transgenic mice expressing both Ppp2ca and Hsp70 showed cardiac hypertrophy, which implicated that Hsp70 functioned as an endogenous regulator of Ppp2ca in the heart. TgHsp70-induced cardiac hypertrophy was significantly inhibited by adeno-Ppp2ca in a dose response fashion. Conclusion: Taken together, HDAC2 forms a complex with PP2A in the absence of hypertrophic stresses and remains inactivated. HDAC2 acetylation results in dissociation of PP2A and thereby phosphorylation, which is maintained by the association with HSP70 during development of cardiac hypertrophy. Hyun-Ki Min and Somy Yoon contributed equally to this work.

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Abstract 1476: Angiotensin II Induced Hypertrophic Response And Oxidative Stress Is Attenuated In Mice Lacking The Gene For Tnf-α

Circulation ◽

10.1161/circ.116.suppl_16.ii_304-b ◽

2007 ◽

Vol 116 (suppl_16) ◽

Author(s):

Srinivas Sriramula ◽

Nithya Mariappan ◽

Elizabeth McILwain ◽

Joseph Francis

Keyword(s):

Oxidative Stress ◽

Angiotensin Ii ◽

Cardiac Hypertrophy ◽

Collagen Type ◽

Resonance Spectroscopy ◽

Type I ◽

Ang Ii ◽

Hypertrophic Response ◽

Tnf Α ◽

And Oxidative Stress

Tumor necrosis factor-alpha (TNF-α) and angiotensin II (Ang II) play an important role in the pathophysiology of cardiovascular disease in part by inducing the cardiac hypertrophic response and oxidative stress. Recently we demonstrated that angiotensin induced hypertensive response is attenuated in mice lacking the gene for TNF-α. In this study, we examined whether Ang II induced cardiac hypertrophy and increased oxidative stress is mediated through TNF-α. Methods and results: Male TNF-α (−/−) and age matched control (WT) mice were subcutaneously implanted with osmotic minipumps containing Ang II (1 μg/kg/min) or saline for 14 days. Human recombinant TNF-α was injected in one group of TNF-α (−/−) mice (10 μg/kg/day) for 14 days. In WT+Ang mice, a temporal increase in blood pressure was observed during the study as measured by radio telemetry transmitters. At the end of the study, echocardiography revealed an increase in thickness and dimensions of left ventricle (LV) and decreased fractional shortening (%FS) in WT+Ang mice. Real time RT-PCR showed that Ang II- infusion resulted in an increase in heart/bodyweight ratio and of cardiac hypertrophy markers ANP and BNP, and profibrotic genes Collagen Type I, Collagen Type II, and TGF-β in WT mice. Electron Spin resonance spectroscopy revealed an increase in total ROS, superoxide and peroxynitrite in the WT+ANG mice when compared to control WT mice. However, these changes were all attenuated in TNF-α (−/−)+Ang mice. Ang II infusion also increased significantly the mRNA expression of gp91Phox, NOX-1, NOX-4 and AT1R in the LV of WT mice, but not in TNF-α (−/−) mice. Interestingly, injection of TNF-α in the TNF-α (−/−) mice, treated with Ang II resulted in increased cardiac hypertrophy and oxidative stress. Conclusions: Findings from the present study suggest that TNF-α plays an important role in the development of cardiac hypertrophy and oxidative stress in Ang II-induced hypertension.

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Abstract 159: Cardiac Hypertrophy and Sudden Death in a Mouse Model of STIM1 Overexpression

Circulation Research ◽

10.1161/res.113.suppl_1.a159 ◽

2013 ◽

Vol 113 (suppl_1) ◽

Author(s):

Sanjeewa A Goonasekera ◽

Jop van Berlo ◽

Adam R Burr ◽

Robert N Correll ◽

Allen J York ◽

...

Keyword(s):

Mouse Model ◽

Cardiac Hypertrophy ◽

Molecular Mechanisms ◽

Ventricular Myocytes ◽

Interstitial Fibrosis ◽

Heart Weight ◽

Activated T Cells ◽

Lung Weight ◽

Tibia Length

Background: STIM1, an ER/SR resident Ca 2+ sensing protein regulates Ca 2+ entry following internal Ca 2+ store depletion in a broad range of tissues and cell types. However their putative roles in excitable tissue such as cardiac myocytes is uncertain. Results: Here we generated a mouse model of STIM1 overexpression in cardiac and skeletal muscle. Western blot analysis suggested approximately 4-6 fold STIM1 overexpression in Tg mouse hearts compared to Ntg littermates. Immunocytochemistry carried out in ventricular myocytes revealed that STIM1 and the cardiac ryanodine receptor (RyR2) co-localize. Functionally, the amplitude of Ca 2+ entry following SR Ca 2+ depletion was 2-fold greater in myocytes isolated from STIM1 Tg mice compared to NTg littermates. Echocardiographic analysis in STIM1 Tg mice showed age dependent remodeling of the myocardium with a significant decrease in fractional shortening at 16 weeks of age (14.4.5±3.8 in STIM1 Tg vs. 36.9±1.5 in Ntg). These changes were accompanied by a significant increase in heart weight to tibia length (13.6 +/- 1.4 vs 6.5 +/- 0.24) and increased lung weight to tibia length ratio (11.6+/- 2.1 vs 8.1 +/- 0.38) in STIM1 Tg mice compared to Ntg littermates. Photometry experiments in isolated ventricular myocytes demonstrated significantly increased Ca 2+ transient amplitude with an unexpected decrease in the SR Ca 2+ load associated with STIM1 overexpression. In addition transgenic mice showed increased calcineurin-nuclear factor of activated T cells (NFAT) activation in vivo, increased CaMKII activity, interstitial fibrosis and exaggerated hypertrophy following two weeks of neuroendocrine agonist or pressure overload stimulation. Conclusion: Our observations suggest that STIM1 overexpression by itself can lead to cardiac hypertrophy and contribute to pathological cardiac remodeling and possibly sudden cardiac death. The molecular mechanisms underlying these phenomena are currently under investigation.

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

Circulation Research ◽

10.1161/res.127.suppl_1.282 ◽

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.

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PKC-β is not necessary for cardiac hypertrophy

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.2001.280.5.h2264 ◽

2001 ◽

Vol 280 (5) ◽

pp. H2264-H2270 ◽

Cited By ~ 37

Author(s):

Brian B. Roman ◽

David L. Geenen ◽

Michael Leitges ◽

Peter M. Buttrick

Keyword(s):

Cardiac Hypertrophy ◽

Gene Knockout ◽

Weight Ratio ◽

Left Ventricular Pressure ◽

Left Ventricular ◽

Heart Weight ◽

Hypertrophic Response ◽

Pathological Hypertrophy ◽

Pkc Β ◽

And Control

Studies in human and rodent models have shown that activation of protein kinase C-β (PKC-β) is associated with the development of pathological hypertrophy, suggesting that ablation of the PKC-β pathway might prevent or reverse cardiac hypertrophy. To explore this, we studied mice with targeted disruption of the PKC-β gene (knockout, KO). There were no detectable differences in expression or distribution of other PKC isoforms between the KO and control hearts as determined by Western blot analysis. Baseline hemodynamics were measured using a closed-chest preparation and there were no differences in heart rate and arterial or left ventricular pressure. Mice were subjected to two independent hypertrophic stimuli: phenylephrine (Phe) at 20 mg · kg−1 · day−1 sq infusion for 3 days, and aortic banding (AoB) for 7 days. KO animals demonstrated an increase in heart weight-to-body weight ratio (Phe, 4.3 ± 0.6 to 6.1 ± 0.4; AoB, 4.0 ± 0.1 to 5.8 ± 0.7) as well as ventricular upregulation of atrial natriuretic factor mRNA analogous to those seen in control animals. These results demonstrate that PKC-β expression is not necessary for the development of cardiac hypertrophy nor does its absence attenuate the hypertrophic response.

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