scholarly journals Overexpression of Heat Shock Protein 70 Improves Cardiac Remodeling and Survival in Protein Phosphatase 2A-Expressing Transgenic Mice with Chronic Heart Failure

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 3180
Author(s):  
Somy Yoon ◽  
Ulrich Gergs ◽  
Julie R. McMullen ◽  
Gwang Hyeon Eom
Keyword(s):  
Heart Failure ◽  
Heat Shock ◽  
Transgenic Mice ◽  
Heat Shock Protein ◽  
Dilated Cardiomyopathy ◽  
Cardiac Remodeling ◽  
Protein Phosphatase ◽  
Postnatal Life ◽  
Free Wall ◽  
Wall Thinning

Heat shock protein (HSP) 70 is a molecular chaperone that regulates protein structure in response to thermal stress. In addition, HSP70 is involved in post-translational modification and is related to the severity of some diseases. Here, we tested the functional relevance of long-lasting HSP70 expression in a model of nonischemic heart failure using protein phosphatase 2 catalytic subunit A (PP2CA)-expressing transgenic mice. These transgenic mice, with cardiac-specific overexpression of PP2CA, abruptly died after 12 weeks of postnatal life. Serial echocardiograms to assess cardiac function revealed that the ejection fraction (EF) was gradually decreased in transgenic PP2CA (TgPP2CA) mice. In addition, PP2CA expression exacerbated systolic dysfunction and LV dilatation, with free wall thinning, which are indicators of fatal dilated cardiomyopathy. Interestingly, simultaneous expression of HSP70 in double transgenic mice (dTg) significantly improved the dilated cardiomyopathy phenotype of TgPP2CA mice. We observed better survival, preserved EF, reduced chamber enlargement, and suppression of free wall thinning. In the proposed molecular mechanism, HSP70 preferentially regulates the phosphorylation of AKT. Phosphorylation of AKT was significantly reduced in TgPP2CA mice but was not significantly lower in dTg mice. Signal crosstalk between AKT and its substrates, in association with HSP70, might be a useful intervention for patients with nonischemic heart failure to suppress cardiac remodeling and improve survival.

106 Antibodies against heat-shock protein 60 and 65 in patients with heart failure

2003 ◽  
Vol 2 (1) ◽  
pp. 13
Author(s):  
L JANOSKUTI ◽  
A ZSARY ◽  
Z FORHECZ ◽  
K KELTAI ◽  
T FENYVESI ◽  
...  
Keyword(s):  
Heart Failure ◽  
Heat Shock ◽  
Heat Shock Protein ◽  
Heat Shock Protein 60 ◽  
Patients With 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

scholarly journals Involvement of Reductive Stress in the Cardiomyopathy in Transgenic Mice With Cardiac-Specific Overexpression of Heat Shock Protein 27

Hypertension ◽  
2010 ◽  
Vol 55 (6) ◽  
pp. 1412-1417 ◽  
Author(s):  
Xia Zhang ◽  
Xiaoyan Min ◽  
Chuanfu Li ◽  
Ivor J. Benjamin ◽  
Bo Qian ◽  
...  
Keyword(s):  
Heat Shock ◽  
Transgenic Mice ◽  
Heat Shock Protein ◽  
Heat Shock Protein 27 ◽  
Reductive Stress

Heat shock protein 27 acts as a predictor of prognosis in chronic heart failure patients

2017 ◽  
Vol 473 ◽  
pp. 127-132 ◽  
Author(s):  
Denise Traxler ◽  
Mitja Lainscak ◽  
Elisabeth Simader ◽  
Hendrik Jan Ankersmit ◽  
Borut Jug
Keyword(s):  
Heart Failure ◽  
Heat Shock ◽  
Chronic Heart Failure ◽  
Heat Shock Protein ◽  
Heat Shock Protein 27 ◽  
Heart Failure Patients

Chronic xanthine oxidase inhibition prevents myofibrillar protein oxidation and preserves cardiac function in a transgenic mouse model of cardiomyopathy

2005 ◽  
Vol 289 (4) ◽  
pp. H1512-H1518 ◽  
Author(s):  
Jennifer G. Duncan ◽  
Rajashree Ravi ◽  
Linda B. Stull ◽  
Anne M. Murphy
Keyword(s):  
Heart Failure ◽  
Mouse Model ◽  
Transgenic Mice ◽  
Dilated Cardiomyopathy ◽  
Xanthine Oxidase ◽  
Protein Oxidation ◽  
Oxidase Activity ◽  
Myofibrillar Protein ◽  
Ventricular Dilation ◽  
Xanthine Oxidase Activity

Heart failure is a clinical syndrome associated with elevated levels of oxygen-derived free radicals. Xanthine oxidase activity is believed to be one source of reactive oxygen species in the failing heart. Interventions designed to reduce oxidative stress are believed to have significant therapeutic potential in heart failure. This study tested the hypothesis that xanthine oxidase activity would be elevated in a mouse model of dilated cardiomyopathy and evaluated the effect of chronic oral allopurinol, an inhibitor of xanthine oxidase, on contractility and progressive ventricular dilation in these mice. Nontransgenic and transgenic mice containing a troponin I truncation were treated with oral allopurinol from 2–4 mo of age. Myocardial xanthine oxidase activity was threefold higher in untreated transgenic mice compared with nontransgenic mice. Analyses of myofilament proteins for modification of carbonyl groups demonstrated myofibrillar protein damage in untreated transgenic mice. Treatment with allopurinol for 2 mo suppressed xanthine oxidase activity and myofibrillar protein oxidation. Allopurinol treatment also alleviated ventricular dilation and preserved shortening fraction in the transgenic animals. In addition, cardiac muscle twitch tension was preserved to 70% of nontransgenic levels in allopurinol-treated transgenic mice, a significant improvement over untreated transgenic mice. These findings indicate that chronic inhibition of xanthine oxidase can alter the progression of heart failure in dilated cardiomyopathy.

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

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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