miR-199-sponge transgenic mice develop physiological cardiac hypertrophy

Introduction: Transgenic mice with transient cardiac expression of constitutively active Galpha q (Gαq-TG) caused progressive heart failure and ventricular arrhythmias after the initiating stimulus becomes undetectable. However, the mechanisms are still unknown. Renin-angiotensin system plays a critical role in the development of cardiac hypertrophy and heart failure. We examined the effects of chronic administration of olmesartan on ventricular function, the number of premature ventricular contractions (PVC), and ventricular remodeling in Gαq-TG mice. Methods and Results: Olmesartan (1 mg/kg/day) or vehicle was chronically administered to Gαq-TG from 6 to 32 weeks of age, and all experiments were performed in mice at the age of 32 weeks. Chronic olmesartan treatment prevented the severe reduction of left ventricular fractional shortening and inhibited ventricular interstitial fibrosis and ventricular myocyte hypertrophy in Gαq-TG. Electrocardiogram demonstrated that premature ventricular contraction (PVC) was frequently (more than 20 beats/min) observed in 9 of 10 vehicle-treated Gαq-TG but in none of 10 olmesartan -treated Gαq-TG. The QT interval was significantly shorter in olmesartan-treated Gαq-TG than vehicle-treated Gαq-TG. CTGF, collagen type 1, ANP, BNP, and β-MHC gene expression was increased in vehicle-treated Gαq-TG. Olmesartan significantly decreased these gene expressions in Gαq-TG. Moreover, protein expressions of canonical transient receptor potential (TRPC) channels 3 and 6 increased in vehicle-treated Gαq-TG hearts. Olmesartan significantly decreased TRPC6 expressions in Gαq-TG. Angiotensin converting enzyme (ACE) 1 and 2 gene expressions were also increased in vehicle-treated Gαq-TG and was not decreased to the control level in olmesartan-treated Gαq-TG. Conclusions: These findings suggest that renin-angiotensin system has an important role in the development of cardiac hypertrophy and heart failure even if the initiating stimulus is different from the activation of renin-angiotensin system.

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Abstract 3773: Myotrophin and the p53 Signaling Cascade in Cardiac Hypertrophy/Heart Failure

Circulation ◽

10.1161/circ.118.suppl_18.s_484-a ◽

2008 ◽

Vol 118 (suppl_18) ◽

Author(s):

Biswajit Das ◽

David Young ◽

Amit Vasanji ◽

Sudhiranjan Gupta ◽

Zoran Popovic ◽

...

Keyword(s):

Heart Failure ◽

Transgenic Mice ◽

Cardiac Hypertrophy ◽

Expression Profiles ◽

Gene Array ◽

Weight Ratio ◽

Signaling Cascade ◽

Mobility Shift ◽

Transgenic Mouse Line ◽

P53 Signaling

Myotrophin (Myo), a 12-kDa protein, stimulates myocyte growth and is a factor in initiating cardiac hypertrophy (CH). Cardiospecific overexpression of Myo in transgenic mice (Myo-Tg) induces hypertrophy that progresses to heart failure (HF). Oligonucleotide gene array revealed upregulation of a p53 homologue gene (EST- AI843106 ) in Myo-Tg mice during HF, indicating that p53 plays an important role during the transition of hypertrophy to HF. To dissect out the mechanisms of p53-mediated Myo-induced CH/HF, we developed a double-transgenic mouse line (p53 −/− /myo +/+ ) by crossing Myo-Tg mice with p53-null mice. The double transgenic mice showed a significant attenuation of cardiac mass compared to Myo-Tg mice (heart weight:body weight ratio; 5.2 ± 0.21 vs. 7.9 ± 0.58, p < 0.001) associated with improved cardiac function and downregulation of ANF expression, suggesting that hypertrophy induced by Myo overexpression is indeed mediated through p53. To elucidate the relationship between p53 and Myo-induced hypertrophy, we performed a Reverse-Transcription Real-Time PCR pathway array on heart tissues from p53 −/− /myo +/+ vs. Myo-Tg mice. A bioinformatic approach, Ingenuity Pathway Analysis TM (IPA), was used to analyze the selected up-/downregulated genes. The IPA network showed that among the up-/downregulated genes, Bcl2, Brca1, Cdkn1a and Myc occupy the nodal position, whereas E2f1 , Pmaip1 , Gadd45a and Pttg1 function as peripheral candidates. The expression profiles of some genes of the p53 pathway were validated by immunoblot analysis. Functional assignment of these selected candidate genes showed that Bcl2, E2f1 and FasL are related to CH/HF, but the function of Gadd45a, Pmaip1, and Vcan is still unknown. Apart from these p53 cascade members, we also found that other molecules (e.g., Jnk, Ras, NF-kB, Cyclin L, and Mek) may be involved in an intricate interplay to stimulate p53-mediated Myo-induced CH. Suppression of NF-kB activity (by electrophoresis mobility shift assay) in p53 −/− /myo +/+ mice compared to Myo-Tg mice indicated involvement of NF-kB, as predicted by IPA, in Myo/p53 cross-talk. Our data suggest that the p53 signaling cascade actively participates in progression of hypertrophy to HF, triggered by overexpression of myotrophin.

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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 080: Eya4 Induces Hypertrophy Via Regulation Of p27kip1

Circulation Research ◽

10.1161/res.113.suppl_1.a080 ◽

2013 ◽

Vol 113 (suppl_1) ◽

Author(s):

Tatjana Williams ◽

Moritz Hundertmark ◽

Peter Nordbeck ◽

Sabine Voll ◽

Melanie Muehlfelder ◽

...

Keyword(s):

Transgenic Mice ◽

Cardiac Hypertrophy ◽

Molecular Mechanisms ◽

Pressure Overload ◽

Dominant Negative ◽

Heart Weight ◽

Dominant Negative Effect ◽

Mutant Form ◽

Cardiac Phenotype ◽

Truncating Mutation

Introduction: E193, a truncating mutation in the transcription cofactor Eyes absent 4 (Eya4) causes hearing impairment followed by heart failure. Here we identified the Eya4 dependent molecular mechanisms leading to the cardiac phenotype in the E193 mutation. Methods and Results: First we showed in vitro that the cyclin-dependent kinase inhibitor protein p27kip1 is a direct target of Eya4/Six1 and is suppressed upon Eya4 overexpression, whereas E193 has a dominant negative effect, releasing Eya4 mediated suppression of p27. We next generated transgenic mice with cardiac specific constitutive overexpression of full-length Eya4 or the mutant form E193. While E193 transgenic mice developed age-dependent DCM, Eya4 mice displayed cardiac hypertrophy already under basal conditions as judged by increases in heart weight and cardiomyocyte cross-sectional areas along with increases in myocardial dimension and mass. These two distinct cardiac phenotypes were even more aggravated upon pressure overload suggesting Eya4 is a regulator of cardiac hypertrophy. We also observed that the activity of Casein Kinase 2-α and the phosphorylation status of HDAC2 were significantly upregulated in the Eya4 transgenic mice, while they were significantly reduced in E193 mice, under baseline conditions and pressure overload. We were also able to identify a new human mutation (E215) with a phenotype comparable to the one seen in E193 patients. Conclusion: Our results implicate that Eya4/Six1 regulates cardiac hypertrophic reactions via p27/CK2-α/HDAC2 and indicate that truncating mutations in Eya4 interfere with this newly established signalling pathway.

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IGF1–PI3K-induced physiological cardiac hypertrophy: Implications for new heart failure therapies, biomarkers, and predicting cardiotoxicity

Journal of Sport and Health Science ◽

10.1016/j.jshs.2020.11.009 ◽

2020 ◽

Author(s):

Sebastian Bass-Stringer ◽

Celeste M.K. Tai ◽

Julie R. McMullen

Keyword(s):

Heart Failure ◽

Cardiac Hypertrophy ◽

Physiological Cardiac Hypertrophy

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Overexpression of antizyme in the hearts of transgenic mice prevents the isoprenaline-induced increase in cardiac ornithine decarboxylase activity and polyamines, but does not prevent cardiac hypertrophy

Biochemical Journal ◽

10.1042/0264-6021:3500645 ◽

2000 ◽

Vol 350 (3) ◽

pp. 645 ◽

Cited By ~ 4

Author(s):

Caroline A. MACKINTOSH ◽

David J. FEITH ◽

Lisa M. SHANTZ ◽

Anthony E. PEGG

Keyword(s):

Transgenic Mice ◽

Cardiac Hypertrophy ◽

Ornithine Decarboxylase ◽

Decarboxylase Activity ◽

Ornithine Decarboxylase Activity

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Ventricular Expression of a MLC-2v-rasFusion Gene Induces Cardiac Hypertrophy and Selective Diastolic Dysfunction in Transgenic Mice

Journal of Biological Chemistry ◽

10.1074/jbc.270.39.23173 ◽

1995 ◽

Vol 270 (39) ◽

pp. 23173-23178 ◽

Cited By ~ 210

Author(s):

John J. Hunter ◽

Nobuaki Tanaka ◽

Howard A. Rockman ◽

John Ross ◽

Kenneth R. Chien

Keyword(s):

Transgenic Mice ◽

Cardiac Hypertrophy ◽

Diastolic Dysfunction

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Gene delivery of medium chain acyl-coenzyme A dehydrogenase induces physiological cardiac hypertrophy and protects against pathological remodelling

Clinical Science ◽

10.1042/cs20171269 ◽

2018 ◽

Vol 132 (3) ◽

pp. 381-397 ◽

Cited By ~ 8

Author(s):

Bianca C. Bernardo ◽

Kate L. Weeks ◽

Thawin Pongsukwechkul ◽

Xiaoming Gao ◽

Helen Kiriazis ◽

...

Keyword(s):

Cardiac Hypertrophy ◽

Coenzyme A ◽

Healthy Adult ◽

Capillary Density ◽

Medium Chain ◽

Adult Mice ◽

Physiological Cardiac Hypertrophy ◽

Chain Acyl ◽

Acyl Coenzyme A

We previously showed that medium chain acyl-coenzyme A dehydrogenase (MCAD, key regulator of fatty acid oxidation) is positively modulated in the heart by the cardioprotective kinase, phosphoinositide 3-kinase (PI3K(p110α)). Disturbances in cardiac metabolism are a feature of heart failure (HF) patients and targeting metabolic defects is considered a potential therapeutic approach. The specific role of MCAD in the adult heart is unknown. To examine the role of MCAD in the heart and to assess the therapeutic potential of increasing MCAD in the failing heart, we developed a gene therapy tool using recombinant adeno-associated viral vectors (rAAV) encoding MCAD. We hypothesised that increasing MCAD expression may recapitulate the cardioprotective properties of PI3K(p110α). rAAV6:MCAD or rAAV6:control was delivered to healthy adult mice and to mice with pre-existing pathological hypertrophy and cardiac dysfunction due to transverse aortic constriction (TAC). In healthy mice, rAAV6:MCAD induced physiological hypertrophy (increase in heart size, normal systolic function and increased capillary density). In response to TAC (~15 weeks), heart weight/tibia length increased by ~60% in control mice and ~45% in rAAV6:MCAD mice compared with sham. This was associated with an increase in cardiomyocyte cross-sectional area in both TAC groups which was similar. However, hypertrophy in TAC rAAV6:MCAD mice was associated with less fibrosis, a trend for increased capillary density and a more favourable molecular profile compared with TAC rAAV6:control mice. In summary, MCAD induced physiological cardiac hypertrophy in healthy adult mice and attenuated features of pathological remodelling in a cardiac disease model.

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