SWI/SNF chromatin remodeling enzymes are associated with cardiac hypertrophy in a genetic rat model of hypertension

Background and Purpose: Calcium/calmodulin-dependent protein kinase II (CaMKII) is a ubiquitous serine/threonine kinase implicated in pathological events such as cardiac hypertrophy. In this study we investigated the role of a specific nuclear isoform of CaMKII in chromatin remodeling and in transcriptional regulation in cardiac muscle. Methods: Comprehensive experimental approaches performed in primary cardiomyocyte cultures were used including chromatin immunoprecipitation assays (ChIP), q-PCR, chromatin remodeling assays, in vitro phosphorylation/transcription assays, production of recombinant adenovirus, siRNA technology, fluorescence microscopy and mass spectrometry. Results: We found that CaMKIIδB targets specific components of chromatin during cardiac hypertrophy and binds to nucleosomes through its association domain in a cooperative model. CaMKIIδB also increased chromatin relaxation, and this action was dependent on its kinase activity. The observation that CaMKIIδB interacts with chromatin suggested to us that histones maybe novel substrates of the kinase in cardiac muscle. To test this hypothesis, we performed in vitro kinase assays and found that histone H3 is a bona fide CaMKIIδB substrate and Ser-10 appears to be a predominant phosphorylation site. Increased histone H3 Ser-10 phosphorylation was observed following hypertrophic stimulation and was not associated with cellular proliferation, whereas depletion of CaMKIIδB significantly reduced histone H3 Ser-10 phosphorylation in primary cardiomyocytes. Interestingly, we found that H3 S10 phosphorylation and recruitment of CaMKIIδB occur at promoters of fetal cardiac genes. To establish the functional link between H3 phosphorylation by CaMKIIδB, chromatin remodeling and transcription activation, we developed an in vitro transcription system and using it we found that CaMKIIδB increased chromatin accessibility and mediated transcription of the Mef2 transcription factor. Conclusion: Taken together, these findings highlight a new role of CaMKIIδB as relevant histone H3 kinase and link for the first time epigenetic changes by CaMKII to cardiac hypertrophy.

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P3486Experimental model for heart failure in rats: apelin-13/apj and bnp-45 gene expression analysis

European Heart Journal ◽

10.1093/eurheartj/ehz745.0354 ◽

2019 ◽

Vol 40 (Supplement_1) ◽

Author(s):

H R Helmi ◽

A P Sunjaya ◽

D Limanan ◽

A R Prijanti ◽

S W A Jusman ◽

...

Keyword(s):

Gene Expression ◽

Heart Failure ◽

Cardiac Hypertrophy ◽

Mrna Expression ◽

Rat Model ◽

Control Group ◽

P Value ◽

Sprague Dawley ◽

Hypoxia Exposure ◽

Systemic Hypoxia

Abstract Background Apelin, an adipokine peptide and its receptor has recently emerged as a key signaling pathway in maintaining cardiac performance at chronic pressure loads. Apelin has been linked to ventricular dysfunction and therefore maybe of pathophysiologic relevance as a candidate biomarker in HF patients. Purpose This study aims to investigate Apelin-13 gene expression and level, and Apelin receptor (APJ) level in a rat model of heart failure induced by chronic systemic hypoxia and their correlation to BNP-45 gene expression and level, the current gold standard biomarker for heart failure, and to cardiac histopathologic changes. The effect of chronic systemic hypoxia on cardiac hypertrophy, remodeling and heart failure parameters is also of interest. Methods Twenty-eight male Sprague-Dawley rats (8–12 weeks of age) were placed in special hypoxic chambers divided into 7 groups – a control group provided with normoxia (atmospheric O2 levels) and 6 exposure groups exposed to hypoxia (8% O2) for 6 hours, 1, 3, 5, 7 and 14 days respectively prior to measurement. Changes in the expression of Apelin and BNP-45 were measured using quantitative real-time PCR, whereas changes in Apelin-13, APJ and BNP-45 levels were measured using ELISA. Histopathology staining using Hematoxylin and Eosin was performed on cardiac tissues post-termination. Results Compared to control, BNP-45 mRNA expression in the hypoxic heart was only significantly different in day 14, whereas, Apelin mRNA expression had showed significantly higher values starting from day 7 onward. This is in line with the evidence of cardiac hypertrophy based on histopathologic examination present from day 7 onwards. BNP-45 and Apelin-13 levels were significantly higher compared to control from day 5 onwards with a peak on day 7. Although significantly higher than control, Apelin-13 and BNP-45 level decreases in day 14 as compared to day 7. Mean APJ levels showed a similar profile with Apelin-13 and BNP-45 levels with a peak in day 7 (4.619 ng/mL). The cardiac Apelin-13 level shows strong significant correlation with BNP-45 levels (r 0.823, p-value 0.0001). There was also a strong significant correlation between APJ receptor levels with Apelin-13 (r 0.9029, p-value 0.001) and BNP-45 (r 0.9062, p-value 0.0009) levels. Apelin-13, APJ and BNP-45 levels also showed strong significant positive correlation to the duration of hypoxia exposure. Conclusion Chronic (≥5 days) and not acute systemic hypoxia in an experimental rat model leads to increase in Apelin-13, APJ and BNP-45 levels. Apelin-13 and BNP-45 were found to significantly increase from 5 days onwards. Apelin mRNA expression was found to show significant increase earlier compared to BNP-45 mRNA expression. Hence, Apelin may serve as a new candidate biomarker for detection of HF due to oxidative stress compared to BNP-45. Exposure to chronic systemic hypoxia can serve as an easily replicable rat model for heart failure. Acknowledgement/Funding Department of Biochemistry and Molecular Biology, Faculty of Medicine, Tarumanagara University, Jakarta, Indonesia

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Rat model of exercise-induced cardiac hypertrophy: hemodynamic characterization using left ventricular pressure-volume analysis

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00108.2013 ◽

2013 ◽

Vol 305 (1) ◽

pp. H124-H134 ◽

Cited By ~ 31

Author(s):

Tamás Radovits ◽

Attila Oláh ◽

Árpád Lux ◽

Balázs Tamás Németh ◽

László Hidi ◽

...

Keyword(s):

Exercise Training ◽

Cardiac Hypertrophy ◽

Rat Model ◽

Left Ventricular ◽

Heart Weight ◽

Stroke Work ◽

Functional Changes ◽

Exercise Induced

Long-term exercise training is associated with characteristic structural and functional changes of the myocardium, termed athlete's heart. Several research groups investigated exercise training-induced left ventricular (LV) hypertrophy in animal models; however, only sporadic data exist about detailed hemodynamics. We aimed to provide functional characterization of exercise-induced cardiac hypertrophy in a rat model using the in vivo method of LV pressure-volume (P-V) analysis. After inducing LV hypertrophy by swim training, we assessed LV morphometry by echocardiography and performed LV P-V analysis using a pressure-conductance microcatheter to investigate in vivo cardiac function. Echocardiography showed LV hypertrophy (LV mass index: 2.41 ± 0.09 vs. 2.03 ± 0.08 g/kg, P < 0.01), which was confirmed by heart weight data and histomorphometry. Invasive hemodynamic measurements showed unaltered heart rate, arterial pressure, and LV end-diastolic volume along with decreased LV end-systolic volume, thus increased stroke volume and ejection fraction (73.7 ± 0.8 vs. 64.1 ± 1.5%, P < 0.01) in trained versus untrained control rats. The P-V loop-derived sensitive, load-independent contractility indexes, such as slope of end-systolic P-V relationship or preload recruitable stroke work (77.0 ± 6.8 vs. 54.3 ± 4.8 mmHg, P = 0.01) were found to be significantly increased. The observed improvement of ventriculoarterial coupling (0.37 ± 0.02 vs. 0.65 ± 0.08, P < 0.01), along with increased LV stroke work and mechanical efficiency, reflects improved mechanoenergetics of exercise-induced cardiac hypertrophy. Despite the significant hypertrophy, we observed unaltered LV stiffness (slope of end-diastolic P-V relationship: 0.043 ± 0.007 vs. 0.040 ± 0.006 mmHg/μl) and improved LV active relaxation (τ: 10.1 ± 0.6 vs. 11.9 ± 0.2 ms, P < 0.01). According to our knowledge, this is the first study that provides characterization of functional changes and hemodynamic relations in exercise-induced cardiac hypertrophy.

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Early Post-fertilization Events in the Rat Model: New Insights on Sperm Decondensation Classification and Chromatin Remodeling Patterning.

Biology of Reproduction ◽

10.1093/biolreprod/78.s1.95 ◽

2008 ◽

Vol 78 (Suppl_1) ◽

pp. 95-95

Author(s):

Lisanne Grenier ◽

Barbara Hales ◽

Bernard Robaire

Keyword(s):

Chromatin Remodeling ◽

Rat Model ◽

Sperm Decondensation

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Angiotensin II type 2 receptor gene transfer elicits cardioprotective effects in an angiotensin II infusion rat model of hypertension

Physiological Genomics ◽

10.1152/physiolgenomics.00170.2004 ◽

2004 ◽

Vol 19 (3) ◽

pp. 255-261 ◽

Cited By ~ 41

Author(s):

Beverly L. Falcón ◽

Jillian M. Stewart ◽

Erick Bourassa ◽

Michael J. Katovich ◽

Glenn Walter ◽

...

Keyword(s):

Angiotensin Ii ◽

Gene Transfer ◽

Cardiac Hypertrophy ◽

Rat Model ◽

Lentiviral Vector ◽

Receptor Gene ◽

Left Ventricular ◽

Heart Weight ◽

Sprague Dawley

The role of the angiotensin II type 2 receptor (AT2R) in cardiovascular physiology remains elusive. We have developed an in vivo lentiviral vector-mediated gene transfer system to study the physiological functions of the AT2R. Our objectives in this study were to determine whether the AT2R influences cardiac hypertrophy and myocardial and perivascular fibrosis in a nongenetic rat model of hypertension. Lentiviral vector containing the AT2R or saline was injected intracardially in 5-day-old Sprague-Dawley rats. This resulted in a persistent overexpression of the AT2R in cardiac tissues. At 15 wk of age, animals were infused with either 200 ng·kg−1·min−1 of angiotensin II or saline by implantation of a 4-wk osmotic minipump. This resulted in an increase in blood pressure (BP) that reached maximal by 2 wk of treatment and was associated with a 123% increase in left ventricular wall thickness (LVWT) and a 129% increase in heart weight to body weight ratios (HW/BW). In addition, the increase in cardiac hypertrophy was associated with a 300% and 158% increase in myocardial and perivascular fibrosis, respectively. Cardiac transduction of the AT2R resulted in an 85% attenuation of LVWT, 91% attenuation of HW/BW, and a 43% decrease in myocardial fibrosis induced by angiotensin infusion. These improvements in cardiac pathology were observed in the absence of attenuation of high BP. Thus our observations indicate that long-term expression of the AT2R in the heart attenuates cardiac hypertrophy and fibrosis in a nongenetic rat model of hypertension.

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Effects of trans-resveratrol on hypertension-induced cardiac hypertrophy using the partially nephrectomized rat model

Clinical and Experimental Pharmacology and Physiology ◽

10.1111/j.1440-1681.2005.04303.x ◽

2005 ◽

Vol 32 (12) ◽

pp. 1049-1054 ◽

Cited By ~ 9

Author(s):

Zhaoping Liu ◽

Yan Song ◽

Xiaopeng Zhang ◽

Zeqing Liu ◽

Wenzhong Zhang ◽

...

Keyword(s):

Cardiac Hypertrophy ◽

Rat Model

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Inhibition of Cardiac Hypertrophy Effects in D-Galactose-Induced Senescent Hearts byAlpinate Oxyphyllae FructusTreatment

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2017/2624384 ◽

2017 ◽

Vol 2017 ◽

pp. 1-12 ◽

Cited By ~ 8

Author(s):

Yung-Ming Chang ◽

Hen-Hong Chang ◽

Hung-Jen Lin ◽

Chin-Chuan Tsai ◽

Chuan-Te Tsai ◽

...

Keyword(s):

Cardiac Hypertrophy ◽

Rat Model ◽

Cerebrovascular Disorders ◽

Treated Group ◽

Left Ventricular ◽

Heart Weight ◽

Dependent Manner ◽

Signaling Mechanism ◽

Aging Rat ◽

Whole Heart

Aging is a complex physiological phenomenon accelerated by ROS accumulation, with multisystem decline and increasing vulnerability to degenerative diseases and death. Cardiac hypertrophy is a key pathophysiological component that accompanies the aging process. Alpinate Oxyphyllae Fructus (Alpinia oxyphyllaMIQ, AOF) is a traditional Chinese medicine, which provides cardioprotective activity against aging, hypertension, and cerebrovascular disorders. In this study, we found the protective effect of AOF against cardiac hypertrophy in D-galactose-induced aging rat model. The results showed that treating rats with D-galactose resulted in pathological hypertrophy as evident from the morphology change, increased left ventricular weight/whole heart weight, and expression of hypertrophy-related markers (MYH7 and BNP). Both concentric and eccentric cardiac hypertrophy signaling proteins were upregulated in aging rat model. However, these pathological changes were significantly improved in AOF treated group (AM and AH) in a dose-dependent manner. AOF negatively modulated D-galactose-induced cardiac hypertrophy signaling mechanism to attenuate ventricular hypertrophy. These enhanced cardioprotective activities following oral administration of AOF reflect the potential use of AOF for antiaging treatments.

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