• The Journal of Internal Korean Medicine
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• v.39 no.4
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• pp.624-636
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• 2018

Objectives: The purpose of this study was to investigate the cardioprotective effect of the potent antioxidant properties of Scrophulariae Radix (SR) aqueous extracts by examining pressure overload (PO) heart failure (HF) induced by transverse aortic constriction (TAC) of C57BL/6 mice. Methods: SR (500, 250, 125 mg/kg) and resveratrol (10 mg/kg) were administered orally once a day for 14 days, after the TAC operation. Changes in mortality, the body and heart weights, histopathology of the heart, and antioxidant defense system of the heart were analyzed. Results: After the TAC operation, increases were observed in mortality, heart weights, left ventricular hypertrophy, and lytic and focal fibrotic histological change, and destruction of the heart antioxidant defense system. However, the HF signs showed dose-dependent inhibition following 14 days of continuous oral treatment with SR. A SR dose of 125 mg/kg gave a similar inhibition to that obtained with resveratrol at 10 mg/kg. Conclusions: Oral administration of SR beneficially improves PO-induced HF following TAC surgery by increasing the activity of the heart antioxidant defense system. The overall effect of SR at 125 mg/kg is similar to the effect of resveratrol at 10 mg/kg. However, more detailed mechanistic studies should be performed by screening of the biologically active compounds in SR.

• Molecules and Cells
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• v.40 no.1
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• pp.66-72
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• 2017

Pathological hypertrophy of the heart is closely associated with endoplasmic reticulum stress (ERS), leading to maladaptations such as myocardial fibrosis, induction of apoptosis, and cardiac dysfunctions. Salubrinal is a known selective inhibitor of protein phosphatase 1 (PP1) complex involving dephosphorylation of phospho-eukaryotic translation initiation factor 2 subunit $(p-eIF2)-{\alpha}$, the key signaling process in the ERS pathway. In this study, the effects of salubrinal were examined on cardiac hypertrophy using the mouse model of transverse aortic constriction (TAC) and cell model of neonatal rat ventricular myocytes (NRVMs). Treatment of TAC-induced mice with salubrinal ($0.5mg{\cdot}kg^{-1}{\cdot}day^{-1}$) alleviated cardiac hypertrophy and tissue fibrosis. Salubrinal also alleviated hypertrophic growth in endothelin 1 (ET1)-treated NRVMs. Therefore, the present results suggest that salubrinal may be a potentially efficacious drug for treating pathological cardiac remodeling.

• The Journal of Korean Medicine
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• v.37 no.2
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• pp.23-35
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• 2016

Objectives: The objective of this study is to demonstrate the cardioprotective effects of Salvia Miltiorrhiza Radix (SMR) on the pressure overload (PO)-induced heart failure (HF) by transverse aortic constriction (TAC) in C57BL/6 mice through possible antioxidant effects. Methods: The mortality, body and heart weights, antioxidant defense system of the heart and histopathology of heart were analyzed. The obtained results were compared with resveratrol, in which potent cardioprotective effects on TAC mice model were already proved at a dose level of 10 mg/kg by antioxidant effects, as reference in this experiment. Results: Significant increases of mortalities, heart weights, and hypertrophic, lytic and focal fibrotic histological changes in the left ventricles were found with defects of heart antioxidant defense systems - the increases of heart cortex MDA contents, decreases of GSH contents, SOD and CAT activities in TAC control mice as compared with sham vehicle control mice, respectively. However, these HF signs induced by TAC surgery through PO and destroys heart antioxidant defense systems were significantly and dose-dependently inhibited by 14 days continuous oral treatment of SMR 500, 250 and 125 mg/kg, similar to those of resveratrol 10 mg/kg in SMR 125 mg/kg. Conclusions: The results obtained in this study propose that oral administration of SMR potently alleviates PO-induced HF by TAC, through augmentation of heart antioxidant defense system.

• The Journal of Internal Korean Medicine
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• v.38 no.6
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• pp.877-890
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• 2017

Objectives: Lonicerae flos (LF), a dried flower part of Lonicera japonica Thunb., has been widely used in Korean medicine as anti-inflammatory and antioxidative agent. The purpose of this study was to determine the cardioprotective effects of LF, through potential antioxidant effects, on the pressure overload (PO)-induced heart failure (HF) in C57BL/6 mice after transverse aortic constriction (TAC) surgery. Methods: Resveratrol (10 mg/kg body weight) or LF (125, 250 or 500 mg/kg body weight) was orally administered, once daily for 14 days, starting 14 days after TAC surgery. Changes in the mortality, body weights, heart weights, histopathology of the heart, and antioxidant defense systems of the heart were analyzed. Results: Marked and noticeable increases of heart weights, mortalities, and hypertrophic, focal, and lytic fibrotic histological changes in the LVs were observed, with destruction of heart antioxidant defense systems after surgery. However, HF signs, induced by TAC surgery through PO, and destruction of heart antioxidant defense systems were significantly and dose-dependently inhibited by 14 days of maintained oral treatment with LF 500, 250 or 125 mg/kg. Treatment with 250 mg/kg LF was comparable to treatment with 10 mg/kg resveratrol. Conclusions: The results in this study suggest that oral administration of LF favorably relieves PO-induced HF following TAC, through increase of heart antioxidant defense systems. The overall effects of 250 mg/kg LF were similar to those of 10 mg/kg resveratrol. More detailed mechanistic studies should be conducted in the future, with screening of the biologically active compounds in LF.

• Journal of Chest Surgery
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• v.50 no.3
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• pp.144-152
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• 2017

Background: The ubiquitin-proteasome system (UPS) is an important pathway of proteolysis in pathologic hypertrophic cardiomyocytes. We hypothesize that MG132, a proteasome inhibitor, might prevent hypertrophic cardiomyopathy (CMP) by blocking the UPS. Nuclear factor kappa-light-chain-enhancer of activated B cells ($NF-{\kappa}B$) and androgen receptor (AR) have been reported to be mediators of CMP and heart failure. This study drew upon pathophysiologic studies and the analysis of $NF-{\kappa}B$ and AR to assess the cardioprotective effects of MG132 in a left ventricular hypertrophy (LVH) rat model. Methods: We constructed a transverse aortic constriction (TAC)-induced LVH rat model with 3 groups: sham (TAC-sham, n=10), control (TAC-cont, n=10), and MG132 administration (TAC-MG132, n=10). MG-132 (0.1 mg/kg) was injected for 4 weeks in the TAC-MG132 group. Pathophysiologic evaluations were performed and the expression of AR and $NF-{\kappa}B$ was measured in the left ventricle. Results: Fibrosis was prevalent in the pathologic examination of the TAC-cont model, and it was reduced in the TAC-MG132 group, although not significantly. Less expression of AR, but not $NF-{\kappa}B$, was found in the TAC-MG132 group than in the TAC-cont group (p<0.05). Conclusion: MG-132 was found to suppress AR in the TAC-CMP model by blocking the UPS, which reduced fibrosis. However, $NF-{\kappa}B$ expression levels were not related to UPS function.

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

• Korean Circulation Journal
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• v.54 no.4
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• pp.172-186
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• 2024

Background and Objectives: Long-term pathological myocardial hypertrophy (MH) seriously affects the normal function of the heart. Dronedarone was reported to attenuate left ventricular hypertrophy of mice. However, the molecular regulatory mechanism of dronedarone in MH is unclear. Methods: Angiotensin II (Ang II) was used to induce cell hypertrophy of H9C2 cells. Transverse aortic constriction (TAC) surgery was performed to establish a rat model of MH. Cell size was evaluated using crystal violet staining and rhodamine phalloidin staining. Reverse transcription quantitative polymerase chain reaction and western blot were performed to detect the mRNA and protein expressions of genes. JASPAR and luciferase activity were conducted to predict and validate interaction between forkhead box O3 (FOXO3) and protein kinase inhibitor alpha (PKIA) promoter. Results: Ang II treatment induced cell hypertrophy and inhibited sirtuin 1 (SIRT1) expression, which were reversed by dronedarone. SIRT1 overexpression or PKIA overexpression enhanced dronedarone-mediated suppression of cell hypertrophy in Ang II-induced H9C2 cells. Mechanistically, SIRT1 elevated FOXO3 expression through SIRT1- mediated deacetylation of FOXO3 and FOXO3 upregulated PKIA expression through interacting with PKIA promoter. Moreover, SIRT1 silencing compromised dronedarone-mediated suppression of cell hypertrophy, while PKIA upregulation abolished the influences of SIRT1 silencing. More importantly, dronedarone improved TAC surgery-induced MH and impairment of cardiac function of rats via affecting SIRT1/FOXO3/PKIA axis. Conclusions: Dronedarone alleviated MH through mediating SIRT1/FOXO3/PKIA axis, which provide more evidences for dronedarone against MH.