• Journal of mucopolysaccharidosis and rare diseases
• /
• v.4 no.1
• /
• pp.21-25
• /
• 2018

Fabry disease is a hereditary lysosomal storage disorder caused by the reduction or absence of lysosomal enzyme alpha-galactosidase A and the accumulation of glycosphingolipids, such as globotriaosylceramide (Gb3), in various organs, including the heart. The prevention of cardiac involvement in Fabry disease can only be achieved by enzyme replacement therapy (ERT), and the method of assessing the efficacy of ERT should be confirmed. Changes in the electrocardiogram, such as the shortening of PQ interval, prolongation of QTc and repolarization abnormalities as well as left ventricular hypertrophy in voltage criteria, can be used to identify Fabry disease patients; however, the usefulness of electrocardiograms for evaluating the efficacy of ERT is limited. The assessment of left ventricular hypertrophy using echocardiography has been established to evaluate the efficacy of ERT during long-term period. A new technique involving speckled tracking method might be useful for detecting early cardiac dysfunction and identifying the effect of ERT for a relatively short period. The estimation of left ventricular hypertrophy using cardiac magnetic resonance (CMR) is also useful for assessing the efficacy of ERT. Identifying late gadolinium enhancement in CMR may affect the effectiveness of ERT, and the new technique of T1 mapping might be useful for monitoring the accumulation of Gb3 during ERT. Histopathology in cardiac biopsy specimens is another potentially useful method for identifying the accumulation of GB3; however, the use of histopathology to evaluate of the efficacy of ERT is limited because of the invasive nature of an endomyocardial biopsy.

• Journal of the Korean Society of Food Science and Nutrition
• /
• v.32 no.5
• /
• pp.700-705
• /
• 2003

Oriental pear was used as treatment of asthma, control of blood pressure tonic medicine vasoactio, diabetes in oriental medicine. In this study, it was investigated that pear pectin effects on cardiovascular system as blood pressure and renin and atrial natriuretic peptide (ANP) in plasma, cardiac hypertrophy. The experiments were performed on Sprague-Dawley rats, 2K1C hypertension model was prepared by constricting the left renal artery with a sliver clip. Animals were then divided into four groups, 5 mg/kg, 10 mg/kg, 15 mg/kg and the control, pear pectin and apple pectin solutions were supplied with them. The blood pressure was more decreased in pear pectin 10 mg/kg than in apple pectin. The plasma ANP was decreased in pear pectin 10 mg/kg, and renin was increased in same concentration of drug. Cardiac hypertrophy had a tendency to decrease in pear pectin 15 mg/kg, but was not statistically significant compared to control group.

• BMB Reports
• /
• v.50 no.4
• /
• pp.208-213
• /
• 2017

Vascular endothelial growth factor (VEGF) is an essential cytokine that has functions in the formation of new blood vessels and regression of cardiac hypertrophy. VEGF/VEGF-receptor-1 (VEGFR1) signaling plays a key role in the regression of cardiac hypertrophy, whereas VEGF/VEGFR2 signaling leads to cardiac hypertrophy. In this study, we identified the prohypertrophic role of miR-374 using neonatal rat ventricular myocytes (NRVMs). Our results showed that overexpression of miR-374 activated G protein-coupled receptor-mediated prohypertrophic pathways by the inhibition of VEGFR1-dependent regression pathways. Luciferase assays revealed that miR-374 could directly target the 3'-untranslated regions of VEGFR1 and cGMP-dependent protein kinase-1. Collectively, these findings demonstrated that miR-374 was a novel pro-hypertrophic microRNA functioning to suppress the VEGFR1-mediated regression pathway.

• Korean Journal of Veterinary Research
• /
• v.44 no.1
• /
• pp.7-13
• /
• 2004

Severe hypertension (>180 mmHg) develops in spontaneously hypertensive rats (SHR) after 12 wk-old; however, it is not clear whether what kinds of molecular mechanism leads to altered cardiac performance following developmental stages in SHR. Also, although the effect of calcineurin (Cn) to promote cardiomyocyte hypertrophy in vivo and in vitro is established, its overall necessity as a hypertrophic mediator is currently an area of ongoing debate. Thus, we have examined i) body weight and blood pressure, ii) differences of expression and distribution of signaling molecules such as Cn, protein kinase B/Akt (PKB/Akt), and extracellular signal-regulated kinase (ERK) between SHR and their age-matched control Wistar-Kyoto (WKY) rats following developmental stages. In 16 wk-old SHR compared with WKY, 2-dimentional echocardiography showed cardiac enlargement and hypertrophy of left ventricle, significantly. Taken together, we suggest that Cn is associated with hereditary cardiac hypertrophy, the process being related to the molecular signaling mechanisms involving PKB/Akt and ERK.

• Molecules and Cells
• /
• v.44 no.7
• /
• pp.500-516
• /
• 2021

Cardiac hypertrophic signaling cascades resulting in heart failure diseases are mediated by protein phosphorylation. Recent developments in mass spectrometry-based phosphoproteomics have led to the identification of thousands of differentially phosphorylated proteins and their phosphorylation sites. However, functional studies of these differentially phosphorylated proteins have not been conducted in a large-scale or high-throughput manner due to a lack of methods capable of revealing the functional relevance of each phosphorylation site. In this study, an integrated approach combining quantitative phosphoproteomics and cell-based functional screening using phosphorylation competition peptides was developed. A pathological cardiac hypertrophy model, junctate-1 transgenic mice and control mice, were analyzed using label-free quantitative phosphoproteomics to identify differentially phosphorylated proteins and sites. A cell-based functional assay system measuring hypertrophic cell growth of neonatal rat ventricle cardiomyocytes (NRVMs) following phenylephrine treatment was applied, and changes in phosphorylation of individual differentially phosphorylated sites were induced by incorporation of phosphorylation competition peptides conjugated with cell-penetrating peptides. Cell-based functional screening against 18 selected phosphorylation sites identified three phosphorylation sites (Ser-98, Ser-179 of Ldb3, and Ser-1146 of palladin) displaying near-complete inhibition of cardiac hypertrophic growth of NRVMs. Changes in phosphorylation levels of Ser-98 and Ser-179 in Ldb3 were further confirmed in NRVMs and other pathological/physiological hypertrophy models, including transverse aortic constriction and swimming models, using site-specific phospho-antibodies. Our integrated approach can be used to identify functionally important phosphorylation sites among differentially phosphorylated sites, and unlike conventional approaches, it is easily applicable for large-scale and/or high-throughput analyses.

• Proceedings of the Korean Biophysical Society Conference
• /
• 2003.06a
• /
• pp.52-52
• /
• 2003

Junctate is a newly identified integral ER/SR membrane $Ca^{2+}$ binding protein, which is an alternative splicing form of the same gene generating aspartyl $\square$-hydroxylase and junctin. To elucidate the functional role of junctate in heart, transgenic (TG) mice overexpressing mouse cardiac junctate-1 under the control of mouse $\square$$^{~}$ myosin heavy chain promoter were generated. Overexpression of junctate in mouse heart resulted in cardiac hypertrophy, increased fibrosis, bradycardia, arrhythmias and impaired contractility. Overexpression of junctate also led to down-regulation of SERCA2, calsequestrin, calreticulin and RyR, but to up-regulation of NCX and PMCA. The SR $Ca^{2+}$ content decreased and the L-type $Ca^{2+}$ current density and the action potential durations increased in TG cardiomyocytes, which could be the cause for the bradycardia in TG heart. The present work has provided an important example of pathogenesis leading to cardiac hypertrophy and arrhythmia, which was caused by impaired $Ca^{2+}$ handling by overexpression of junctate in heart.n heart.

• Clinical and Experimental Pediatrics
• /
• v.52 no.7
• /
• pp.752-755
• /
• 2009

It is well known that hemodynamic load is one of the most important determinants of cardiac structure and function. Circadian variations in blood pressure (BP) are usually accompanied by consensual changes in peripheral resistance and/or cardiac output. In recent years, reduction in circadian variations in BP and, in particular, loss of nocturnal decline of BP were observed in hypertensive patients with left ventricular hypertrophy (LVH). The patients with only a slight or no loss of nocturnal decline of BP were considered "non-dippers". Regression of LVH was observed after prolonged antihypertensive therapy. Restoration of the circadian rhythm of BP was also observed. However, the classification of patients into "dippers" and "non-dippers" is arbitrary and poorly standardized and repeatable, and in the recent studies, most hypertensive patients with LVH were "dippers". Therefore, we should be particularly cautious about the conclusions drawn using this index. On the other hand, reduced activity of low-pressure cardiopulmonary baroreceptors and impaired day-to-night modulation of autonomic nervous system activity were observed in patients with only LVH. Therefore, alterations in cardiac structure may impair BP modulation. On the other hand, the reverse can also be trueprimary alterations in BP modulation, through a persistently elevated afterload, can increase cardiac mass. Thus, the interrelationship between cardiac structure and BP modulation is complex. Hence, new and more specific methods of evaluating circadian changes in BP are needed to better clarify the abovementioned reciprocal influences.

• The Korean Journal of Physiology and Pharmacology
• /
• v.5 no.5
• /
• pp.413-421
• /
• 2001

An impaired smooth muscle cell (SMC) relaxation of coronary artery by alteration of $K^+$ channels would be the most potential explanation for reduced coronary reserve in left ventricular hypertrophy (LVH), however, this possibility has not been investigated. We performed morphometrical analysis of the coronary artery under electron microscopy and measured $Ca^{2+}-activated\;K\;(K_{Ca})$ currents and delayed rectifier K $(K_{dr})$ currents by whole-cell and inside-out patch-clamp technique in single coronary arterial SMCs from rabbits subjected to isoprenaline-induced cardiac hypertrophy. Coronary arterial SMCs underwent significant changes in ultrastructure. The unitary current amplitude and the open-state probability of $K_{Ca}$ channel were significantly reduced in hypertrophy without open-time and closed-time kinetic. The concentration-response curve of $K_{Ca}$ channel to $Ca^{2+}$ is shifted to the right in hypertrophy. The reduction in the mean single channel current and increase in the open channel noise of $K_{Ca}$ channel by TEA were more sensitive in hypertrophy. $K_{dr}$ current density is significantly reduced in hypertrophy without activation and inactivation kinetics. The sensitivity of $K_{dr}$ current on 4-AP is significantly increased in hypertrophy. This is the first study to report evidence for alterations of $K_{Ca}$ channels and $K_{dr}$ channels in coronary SMCs with LVH. The findings may provide some insight into mechanism of the reduced coronary reserve in LVH.

• Reproductive and Developmental Biology
• /
• v.35 no.2
• /
• pp.159-165
• /
• 2011

To explore the role of histone deactylase (HDAC) activation in an in vivo model of hypertrophy, we studied the effects of Trichostatin A (TSA). TSA subjected to thoracic aortic banding (TAB)-induced pressure stress in mice. In histological observations, TAB in treated mice showed a significant hypertrophic response, whereas the sham operation remained nearly normal structure with partially blunted hypertrophy. TSA treatment had no effect (measured as HW/BW) on sham-operated animals. TAB animals treated with vehicle manifested a robust ~50% hypertrophic response (p<0.05 vs sham). TAB mice treated with 2 mg/kg/day TSA manifested a blunted growth responses, which was significantly diminished (p<0.05) compared with vehicle-treated TAB mice. TAB mice treated with a lower dose of TSA (0.5 mg/kg/day) manifested a similar blunting of hypertrophic growth (~25% increase in heart mass). Furthermore, to determine activity duration of TSA in vitro, 1 nM TSA was added to H9c2 cells. Histone acetylation was initiated at 4 hr after treatment, and it was peak up to 18 hr, then followed by significantly reduced to 30 hr. We also analyzed the expression of p53 following TSA treatment, wherein p53 expression was elevated at 4 hr, and it was maintained to 24 hr after treatment. ERK was activated at 8 hr, and maintained till 30 hr after treatment suggesting an intracellular signaling interaction between TSA and p53 expression Taken together, it is suggested that HDAC activation is required for pressure-overload growth of the heart. Eventually, these data suggest that histone acetylation may be a novel target for therapeutic intervention in pressure-overloaded cardiac hypertrophy.

• Korean Journal of Veterinary Research
• /
• v.45 no.4
• /
• pp.537-544
• /
• 2005

We have examined distribution and expression of caveolin-3 (cav-3), one of three caveolin isoforms from 16-wks-old spontaneously hypertensive rats (SHR) compared with age-matched control wistar-kyoto (WKY) rats. The expression of cav-3 was increased, whereas expression of PKB/Akt and calcineurin (Cn) was not changed in cardiac tissues of SHR compared to WKY rats. Interestingly, expression of cav-3, PKB/Akt and Cn were decreased in plasma membrane fraction in SHR compared to WKY rats. In H9c2 cardiomyoblast cells treated with phenylephrine ($50{\mu}M$, 48hr) or isoproterenol ($10{\mu}M$, 48hr), the expression of cav-3 was markedly enhanced compared to nontreated cells. Upon immunofluorescence analysis, cav-3 was localized in plasma membrane of control H9c2 cells. However phenylephrine or isoproterenol treatment caused translocation of cav-3 to perinuclear region. These results suggest that cav-3 plays as positive regulators in the development of hypertrophy in cardiac tissues of SHR rats.