Angiotensin II Facilitates Matrix Metalloproteinase-9-Mediated Myosin Light Chain Kinase Degradation in Pressure Overload-Induced Cardiac Hypertrophy

Wang, Shun; Cheng, Mian; Hu, Zhengqing; Huang, Shan; Zou, Qiang; Lai, Xin; Liu, Beilei; Jiang, Hong; Huang, Congxin; Wu, Gang

doi:10.1159/000486066

Cited by 12 publications

(9 citation statements)

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“…15,39 In an earlier study, we found that MLCK and p-MLC2 were involved in CH due to their degradation by AngII. 40 The overexpression of cMLCK in cardiac myocytes promotes sarcomere organization, which is an adaptive response to hypertrophic stimuli during early CH, while the knockdown of cMLCK resulted in sarcomeric disorganization. 41 Moreover, the expression level of cMLCK is reduced in animal models of MI.…”

Section: Mir-200c Directly Targeted Mlckmentioning

confidence: 99%

Down‐regulation of miR‐200c attenuates AngII‐induced cardiac hypertrophy via targeting the MLCK‐mediated pathway

Huang

Cheng

Guo

et al. 2019

J Cellular Molecular Medi

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Background MicroRNAs (miRNAs) have been shown to commonly contribute to cardiac hypertrophy (CH). The aim of this study was to test the hypothesis that miR‐200c plays an important role in the progression of CH by targeting myosin light chain kinase (MLCK/MYLK). Methods and results Cardiac hypertrophy was induced by aortic banding (AB) in rats. Cellular hypertrophy in neonatal rat cardiomyocytes (NCMs) was induced by AngII treatment. Echocardiography, histology and molecular measurements were used to assess the results of the experiments. The levels of apoptosis and reactive oxygen species (ROS) were also measured. Quantitative real‐time PCR (qRT‐PCR) and Western blotting were used to measure mRNA and protein levels respectively. The present results showed that miR‐200c expression was increased in response to CH both in vivo and in vitro. The down‐regulation of miRNA‐200c by a specific inhibitor markedly ameliorated CH resulting from AngII treatment, and the mRNA levels of atrial natriuretic peptide, brain natriuretic peptide and β‐myosin heavy chain were simultaneously decreased. Notably, minimal apoptosis and ROS accumulation were identified in AngII‐induced hypertrophic cardiomyocytes. Conversely, the up‐regulation of miR‐200c using specific mimics reversed these effects. Mechanistic investigations demonstrated that the MLCK gene is a direct target of miR‐200c; an increase in miR‐200c levels led to a decrease in the expression of MLCK and its downstream effector, p‐MLC2, while miR‐200c inhibition increased the expression of these proteins. Furthermore, inhibiting MLCK impaired the anti‐hypertrophic effects contributions produced by the knockdown of miR‐200c. Conclusion Our studies suggest that miR‐200c may serve as a potential therapeutic target that could delay hypertrophy. We have also uncovered a relationship between miR‐200c and MLCK, identifying MLCK as a direct mediator of miR‐200c.

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Section: Mir-200c Directly Targeted Mlckmentioning

confidence: 99%

Down‐regulation of miR‐200c attenuates AngII‐induced cardiac hypertrophy via targeting the MLCK‐mediated pathway

Huang

Cheng

Guo

et al. 2019

J Cellular Molecular Medi

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“…All animals used in this study were postnatal days 1–3 Sprague-Dawley (SD) rats, which were supplied by the Experiment Animal Centre of Wuhan University. We also followed the methods reported in the literature;[ 20 ] NRCMs were isolated from the hearts of SD rat pups on postnatal days 1–3 and were cultured to <98% purity. [ 21 ] Briefly, SD rats were sacrificed by swift decapitation, and the hearts were excised and minced immediately.…”

Section: Ethodsmentioning

confidence: 99%

Effect of the Shensong Yangxin Capsule on Energy Metabolism in Angiotensin II-Induced Cardiac Hypertrophy

Liu

Cheng

Huang

et al. 2018

Chinese Medical Journal

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Background:Shensong Yangxin Capsule (SSYX), traditional Chinese medicine, has been used to treat arrhythmias, angina, cardiac remodeling, cardiac fibrosis, and so on, but its effect on cardiac energy metabolism is still not clear. The objective of this study was to investigate the effects of SSYX on myocardium energy metabolism in angiotensin (Ang) II-induced cardiac hypertrophy.Methods:We used 2 μl (10−6 mol/L) AngII to treat neonatal rat cardiomyocytes (NRCMs) for 48 h. Myocardial α-actinin staining showed that the myocardial cell volume increased. Expression of the cardiac hypertrophic marker-brain natriuretic peptide (BNP) messenger RNA (mRNA) also increased by real-time polymerase chain reaction (PCR). Therefore, it can be assumed that the model of hypertrophic cardiomyocytes was successfully constructed. Then, NRCMs were treated with 1 μl of different concentrations of SSYX (0.25, 0.5, and 1.0 μg/ml) for another 24 h. To explore the time-depend effect of SSYX on energy metabolism, 0.5 μg/ml SSYX was added into cells for 0, 6, 12, 24, and 48 h. Mitochondria was assessed by MitoTracker staining and confocal microscopy. mRNA and protein expression of mitochondrial biogenesis-related genes – Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), energy balance key factor – adenosine monophosphate-activated protein kinase (AMPK), fatty acids oxidation factor – carnitine palmitoyltransferase-1 (CPT-1), and glucose oxidation factor – glucose transporter- 4 (GLUT-4) were measured by PCR and Western blotting analysis.Results:With the increase in the concentration of SSYX (from 0.25 to 1.0 μg/ml), an increased mitochondrial density in AngII-induced cardiomyocytes was found compared to that of those treated with AngII only (0.25 μg/ml, 18.3300 ± 0.8895 vs. 24.4900 ± 0.9041, t = 10.240, P < 0.0001; 0.5 μg/ml, 18.3300 ± 0.8895 vs. 25.9800 ± 0.8187, t = 12.710, P < 0.0001; and 1.0 μg/ml, 18.3300 ± 0.8895 vs. 24.2900 ± 1.3120, t = 9.902, P < 0.0001; n = 5 per dosage group). SSYX also increased the mRNA and protein expression of PGC-1α (0.25 μg/ml, 0.8892 ± 0.0848 vs. 1.0970 ± 0.0994, t = 4.319, P = 0.0013; 0.5 μg/ml, 0.8892 ± 0.0848 vs. 1.2330 ± 0.0564, t = 7.150, P < 0.0001; and 1.0 μg/ml, 0.8892 ± 0.0848 vs. 1.1640 ± 0.0755, t = 5.720, P < 0.0001; n = 5 per dosage group), AMPK (0.25 μg/ml, 0.8872 ± 0.0779 vs. 1.1500 ± 0.0507, t = 7.239, P < 0.0001; 0.5 μg/ml, 0.8872 ± 0.0779 vs. 1.2280 ± 0.0623, t = 9.379, P < 0.0001; and 1.0 μg/ml, 0.8872 ± 0.0779 vs. 1.3020 ± 0.0450, t = 11.400, P < 0.0001; n = 5 per dosage group), CPT-1 (1.0 μg/ml, 0.7348 ± 0.0594 vs. 0.9880 ± 0.0851, t = 4.994, P = 0.0007, n = 5), and GLUT-4 (0.5 μg/ml, 1.5640 ± 0.0599 vs. 1.7720 ± 0.0660, t = 3.783, P = 0.0117; 1.0 μg/ml, 1.5640 ± 0.0599 vs. 2.0490 ± 0.1280, t = 8.808, P < 0.0001; n = 5 per dosage group). The effect became more obvious with the increasing concentration of SSYX. When 0.5 μg/ml SSYX was added into cells for 0, 6, 12, 24, and 48 h, the expression of AMPK (6 h, 14.6100 ± 0.6205 vs. 16.5200 ± 0.7450, t = 3.456, P = 0.0250...

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“…For example, peroxisome proliferator-activated receptors α and γ ligands downregulate the MMP-9 expression in lipopolysaccharide-treated human monocytic THP-1 cells (Shu et al, 2000). Since angiotensin II induces MMP-9 expression and angiotensin II-induced cardiomyocyte hypertrophy is mediated by MMP-9, tissue protective actions by RAS inhibitors may be at least in part by MMP-9 inhibition (Wang, Cheng, et al, 2017). In addition to these agents, suppression of inflammation by lifestyle modification and treatment of diseases results in the decline in inflammatory cells, which are the major source of MMP-9.…”

Section: Discussionmentioning

confidence: 99%

“…MMP-9 deletion attenuates LV remodeling and dysfunction after transverse aortic constriction (Heymans et al, 2005). The adverse effect of MMP-9 in the pressure-overloaded heart is strengthened by a recent study that demonstrates that angiotensin II facilitates cardiac hypertrophy through MMP-9 activation (Wang et al, 2017).…”

Section: Potential Therapeutic Targets For Cvd and Ckd In The Elderlymentioning

confidence: 99%

Extracellular matrix roles in cardiorenal fibrosis: Potential therapeutic targets for CVD and CKD in the elderly

Toba

Lindsey

2019

Pharmacology & Therapeutics

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Whereas hypertension, diabetes, and dyslipidemia are age-related risk factors for cardiovascular disease (CVD) and chronic kidney disease (CKD), aging alone is an independent risk factor. With advancing age, the heart and kidney gradually but significantly undergo inflammation and subsequent fibrosis, which eventually results in an irreversible decline in organ physiology. Through cardiorenal network interactions, cardiac dysfunction leads to and responds to renal injury, and both facilitate aging effects. Thus, a comprehensive strategy is needed to evaluate the cardiorenal aging network. Common hallmarks shared across systems include extracellular matrix (ECM) accumulation, along with upregulation of matrix metalloproteinases (MMPs) including MMP-9. The wide range of MMP-9 substrates, including ECM components and inflammatory cytokines, implicates MMP-9 in a variety of pathological and age-related processes. In particular, there is strong evidence that inflammatory cell-derived MMP-9 exacerbates cardiorenal aging. This review explores the potential therapeutic targets against CVD and CKD in the elderly, focusing on ECM and MMP roles.

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Angiotensin II Facilitates Matrix Metalloproteinase-9-Mediated Myosin Light Chain Kinase Degradation in Pressure Overload-Induced Cardiac Hypertrophy

Cited by 12 publications

References 57 publications

Down‐regulation of miR‐200c attenuates AngII‐induced cardiac hypertrophy via targeting the MLCK‐mediated pathway

Down‐regulation of miR‐200c attenuates AngII‐induced cardiac hypertrophy via targeting the MLCK‐mediated pathway

Effect of the Shensong Yangxin Capsule on Energy Metabolism in Angiotensin II-Induced Cardiac Hypertrophy

Extracellular matrix roles in cardiorenal fibrosis: Potential therapeutic targets for CVD and CKD in the elderly

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