Casein Kinase-2 Interacting Protein-1 Regulates Physiological Cardiac Hypertrophy via Inhibition of Histone Deacetylase 4 Phosphorylation

Different kinds of mechanical stimuli acting on the heart lead to different myocardial phenotypes. Physiological stress, such as exercise, leads to adaptive cardiac hypertrophy, which is characterized by a normal cardiac structure and improved cardiac function. Pathological stress, such as sustained cardiac pressure overload, causes maladaptive cardiac remodeling and, eventually, heart failure. Casein kinase-2 interacting protein-1 (CKIP-1) is an important regulator of pathological cardiac remodeling. However, the role of CKIP-1 in physiological cardiac hypertrophy is unknown. We subjected wild-type (WT) mice to a swimming exercise program for 21 days, which caused an increase in myocardial CKIP-1 protein and mRNA expression. We then subjected CKIP-1 knockout (KO) mice and myocardial-specific CKIP-1-overexpressing mice to the 21-day swimming exercise program. Histological and echocardiography analyses revealed that CKIP-1 KO mice underwent pathological cardiac remodeling after swimming, whereas the CKIP-1-overexpressing mice had a similar cardiac phenotype to the WT controls. Histone deacetylase 4 (HDAC4) is a key molecule in the signaling cascade associated with pathological hypertrophy; the phosphorylation levels of HDAC4 were markedly higher in CKIP-1 KO mouse hearts after the swimming exercise program. The phosphorylation levels of HDAC4 did not change after swimming in the hearts of CKIP-1-overexpressing or WT mice. Our results indicate that swimming, a mechanical stress that leads to physiological hypertrophy, triggers pathological cardiac remodeling in CKIP-1 KO mice. CKIP-1 is necessary for physiological cardiac hypertrophy in vivo, and for modulating the phosphorylation level of HDAC4 after physiological stress. Genetically engineering CKIP-1 expression affected heart health in response to exercise.

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Abstract 97: Histone Deacetylase Inhibition Prevents Cardiac Remodeling in Mice Carrying the Disruption of Guanylyl Cyclase/natriuretic Peptide Receptor-A Gene

Hypertension ◽

10.1161/hyp.62.suppl_1.a97 ◽

2013 ◽

Vol 62 (suppl_1) ◽

Author(s):

Umadevi Subramanian ◽

Prerna Kumar ◽

Kailash N Pandey

Keyword(s):

Cardiac Hypertrophy ◽

Histone Deacetylase ◽

Sodium Butyrate ◽

Cardiac Remodeling ◽

Regulation Of Gene Expression ◽

Heart Weight ◽

Marker Genes ◽

Dependent Manner ◽

Histone Deacetylase Inhibition ◽

Hdac Activity

Regulation of gene expression plays an obligatorily role in the modification of chromatin structure that dynamically attenuates cardiac hypertrophy. In order to culminate the role of epigenetic regulators in the heart tissue, the current study was undertaken to elucidate the effect of histone deacetylase (HDAC) inhibitor, sodium butyrate (SB) in cardiac remodeling process of Npr1 (coding for GC-A/NPRA) gene-targeted mice. Wild type ( Npr1 +/+ , 2-copy), gene-disrupted ( Npr1 +/- , 1-copy), and gene-duplicated ( Npr1 ++/+- , 3-copy) mice were administered intraperitoneally with SB (0.5 mg/kg/day) for 2 weeks (8 mice/group). Mice with gene-disruption ( Npr1 +/- , 1-copy) exhibited the increase in cardiac hypertrophy, heart weight/body weight (HW/BW) ratio (6.9 ± 0.2), and systolic blood pressure (SBP, 121.5 ± 4 mmHg) compared with 2-copy (HW/BW, 5.1 ± 0.2; SBP; 100.9 ± 6 mmHg) and 3-copy (HW/BW, 4.7 ± 0.1; SBP, 89.4 ± 2 mmHg) mice. In addition, an increased activity of HDAC (3-fold, p<0.01) and decreased activity of histone acetyltransferases (HAT) (2.5-fold, p<0.01) were found in untreated 1-copy mice hearts. Whereas, 1-copy mice treated with SB showed reduced HW/BW ratio (5.7 ± 0.3), SBP (SB, 101.2 ± 2), HDAC activity (p<0.01) and improved HAT activity (3-fold, p<0.001). Also, a stimulatory effect on HAT activity was observed in SB treated 2-copy (30%, p<0.01) and 3-copy (50%, p<0.01) mice. Furthermore, Npr1 +/- mice showed a significant increase in the expression of hypertrophic marker genes such as β-myosin heavy chain (β-MHC, 2-fold), α-skeletal actin (α-SK, 2-fold), c-fos (2.5-fold), and c-jun (3-fold) compared to untreated 2-copy and 3-copy mice. A substantial attenuation in the expression of hypertrophic markers (β-MHC, 2.5-fold; α-SK, 2.4-fold) and matrix genes (MMP-2, p<0.01; MMP-9, p<0.01) was found in SB-treated Npr1 +/- mice. The basal expression levels of matrix proteins were also significantly reduced in 2-copy and 3-copy mice hearts. The results show that sodium butyrate-dependent inhibition of HDAC activity attenuates cardiac hypertrophy and fibrosis by improving HAT activity suggesting that chromatin modification can prevent cardiac remodeling process in a Npr1 gene-dose-dependent manner.

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Effect of Swimming Exercise Program on TNF-α, body weight and pulse transmit time in obese women

Korean Journal of Sports Science ◽

10.35159/kjss.2017.10.26.5.979 ◽

2017 ◽

Vol 26 (5) ◽

pp. 979-987

Author(s):

Seo-Hyung Lee ◽

Jeoung-Yun Lee

Keyword(s):

Body Weight ◽

Exercise Program ◽

Swimming Exercise ◽

Obese Women ◽

Tnf Α

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Statins as the Controlling Agents for Non-Hodgkin's Lymphomas via Increasing the Casein Kinase 2 Interacting Protein-1: A Hypothesis

Current Drug Discovery Technologies ◽

10.2174/1570163816666190628165200 ◽

2020 ◽

Vol 17 (5) ◽

pp. 616-618

Author(s):

Kimia Kazemi ◽

Negin Mozafari ◽

Hajar Ashrafi ◽

Pedram Rafiei ◽

Amir Azadi

Keyword(s):

Cell Proliferation ◽

Mevalonate Pathway ◽

Casein Kinase ◽

Casein Kinase 2 ◽

Interacting Protein ◽

Akt Phosphorylation ◽

Anticancer Properties ◽

Proliferation And Apoptosis ◽

Cellular Signaling Pathway ◽

Hodgkin's Lymphomas

Background: Non-Hodgkin's lymphomas (NHL), derived from B- or T-cell, consist of a heterogeneous group of malignant lymphoproliferative disorders. Knockdown of Casein kinase 2 interacting protein-1 (CKIP-1) in NHL promoted cell proliferation and inhibited apoptosis via enhancing phosphorylated Protein Kinase B (PKB or AKT) expression. Statins are the class of drugs that inhibit the ratelimiting step of the mevalonate pathway, which is essential for the biosynthesis of various compounds, including cholesterol. Also, statins have anticancer properties being mediated by different mechanisms. Methods: A search on databases like Scopus and PubMed with keywords such as statin and non- Hodgkin's lymphomas was performed and Kyoto Encyclopedia of Genes and Genomes (KEGG) website was used to evaluate and reconfirm the involved cellular signaling pathway. Results: CKIP-1 is involved in the regulation of cell proliferation and apoptosis while plays an important role in many cancers. We can hypothesize that statins may increase the expression levels of CKIP-1 which could contribute to the reductions in phospho-AKT level. Hence, they may ameliorate the NHL patients via suppressing AKT phosphorylation and increasing CKIP- expression. Conclusion: Present review confirms the positive effect of statins on NHL by increasing CKIP-1 and reducing cell proliferation, subsequently.

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Inhibition of the water channel aquaporin-1 prevents myocardial remodeling by blocking the transmembrane transport of hydrogen peroxide

European Heart Journal ◽

10.1093/ehjci/ehaa946.3665 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

V Montiel ◽

R Bella ◽

L Michel ◽

E Robinson ◽

J.C Jonas ◽

...

Keyword(s):

Hydrogen Peroxide ◽

Cardiac Hypertrophy ◽

Cardiac Myocytes ◽

Cardiac Remodeling ◽

Cardiac Myocyte ◽

Water Channel ◽

Transmembrane Transport ◽

Funding Source ◽

Water Pore

Abstract Background Pathological remodeling of the myocardium has long been known to involve oxidant signaling, but so far, strategies using systemic anti-oxidants have generally failed to prevent it. Aquaporins are a family of transmembrane water channels with thirteen isoforms currently known. Some isoforms have been implicated in oxidant signaling. AQP1 is the most abundant aquaporin in cardiovascular tissues but its specific role in cardiac remodeling remains unknown. Purpose We tested the role of AQP1 as a key regulator of oxidant-mediated cardiac remodeling amenable to targeted pharmacological therapy. Methods We used mice with genetic deletion of Aqp1 (and wild-type littermate), as well as primary isolates from the same mice and human iPSC/Engineered Heart Tissue to test the role of AQP1 in pro-hypertrophic signaling. Human cardiac myocyte-specific (PCM1+) expression of AQP's and genes involved in hypertrophic remodeling was studied by RNAseq and bioinformatic GO pathway analysis. Results RNA sequencing from human cardiac myocytes revealed that the archetypal AQP1 is a major isoform. AQP1 expression correlates with the severity of hypertrophic remodeling in patients with aortic stenosis. The AQP1 channel was detected at the plasma membrane of human and mouse cardiac myocytes from hypertrophic hearts, where it colocalizes with the NADPH oxidase-2 (NOX2) and caveolin-3. We show that hydrogen peroxide (H2O2), produced extracellularly, is necessary for the hypertrophic response of isolated cardiac myocytes and that AQP1 facilitates the transmembrane transport of H2O2 through its water pore, resulting in activation of oxidant-sensitive kinases in cardiac myocytes. Structural analysis of the amino acid residues lining the water pore of AQP1 supports its permeation by H2O2. Deletion of Aqp1 or selective blockade of AQP1 intra-subunit pore (with Bacopaside II) inhibits H2O2 transport in mouse and human cells and rescues the myocyte hypertrophy in human induced pluripotent stem cell-derived engineered heart muscle. This protective effect is due to loss of transmembrane transport of H2O2, but not water, through the intra-subunit pore of AQP1. Treatment of mice with clinically-approved Bacopaside extract (CDRI08) inhibitor of AQP1 attenuates cardiac hypertrophy and fibrosis. Conclusion We provide the first demonstration that AQP1 functions as an aqua-peroxiporin in primary rodent and human cardiac parenchymal cells. We show that cardiac hypertrophy is mediated by the transmembrane transport of H2O2 through the AQP1 water channel. Our studies open the way to complement the therapeutic armamentarium with specific blockers of AQP1 for the prevention of adverse remodeling in many cardiovascular diseases leading to heart failure. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): FRS-FNRS, Welbio

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Oxidative Stress as A Mechanism for Functional Alterations in Cardiac Hypertrophy and Heart Failure

Antioxidants ◽

10.3390/antiox10060931 ◽

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.

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