Neonatal Death and Heart Failure in Mouse with Transgenic HSP60 Expression

Chen, Tsung‐Hsien; Liu, Shan-Wen; Chen, Mei‐Ru; Cho, Kuan-Hung; Chen, Tzu-Yin; Chu, Pao‐Hsien; Kao, Yu-Ying; Hsu, Charles Ching–Hsiang; Lin, Keh Ming

doi:10.1155/2015/539805

Cited by 8 publications

(11 citation statements)

References 39 publications

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“…Interestingly, the impacts of intracellular HSP60 on heart remains controversial. Transgenic HSP60 expression in the embryonic stage causes neonatal death in mice, accompanied with increased apoptosis and myocyte degeneration that possibly contributes to neonatal heart failure [48]. In contrast, intracellular HSP60 is low expressed in diabetic heart [49].…”

Section: Discussionmentioning

confidence: 99%

Hypertrophic adipocyte-derived exosomal miR-802-5p contributes to insulin resistance in cardiac myocytes through targeting HSP60

Wen

et al. 2020

Preprint

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Background : Epicardial adipose tissue (EAT) is implicated in insulin resistance, which has been recognized as a strongest predictor of the development of diabetic cardiomyopathy and subsequent heart failure. However, the underlying mechanism remains incompletely understood. Herein, we investigated the effect of hypertrophic adipocytes on cardiac insulin resistance. Methods : Palmitate was used to induce hypertrophic 3T3-L1 adipocytes. Exosomes were purified from normal control or hypertrophic 3T3-L1 adipocyte-associated conditioned medium. Exosome-exposed neonatal rat ventricular myocytes (NRVMs) were treated with insulin to investigate the effects of exosomes on insulin signaling. Insulin sensitivity was evaluated by measuring insulin-stimulated Akt phosphorylation and glucose uptake. SiRNA techniques were used to downregulate protein levels and its efficiency was evaluated by western blot.Results : Hypertrophic adipocyte-derived exosomes (h-Exo) induced insulin resistance in NRVMs. Furthermore, h-Exo high-expressed miR-802-5p. Insulin sensitivity of NRVMs was impaired by miR-802-5p mimic but improved by its inhibitor. TargetScan and luciferase reporter assays revealed that heat shock protein 60 (HSP60) was a direct target of miR-802-5p. Both h-Exo and miR-802-5p mimic could downregulate HSP60 protein levels. In addition, HSP60 silencing induced insulin resistance and mitigated the insulin-sensitizing effects of adiponectin. HSP60 depletion also significantly increased the expression levels of CHOP, a marker of the unfolded protein response (UPR), and enhanced oxidative stress, accompanied by the increased phosphorylation of JNK and IRS-1 Ser307. Inhibition of both miR-802-5p and endocytosis abolished the impacts of HSP60 knockdown on the UPR and oxidative stress. Conclusion : Hypertrophic adipocyte-derived exosomal miR-802-5p caused cardiac insulin resistance in NRVMs through downregulating HSP60. These findings provide a novel mechanism by which EAT impairs cardiac function.

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Section: Discussionmentioning

confidence: 99%

Hypertrophic adipocyte-derived exosomal miR-802-5p contributes to insulin resistance in cardiac myocytes through targeting HSP60

Wen

et al. 2020

Preprint

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“…Since several heat shock proteins were observed to be involved in cardiovascular diseases, it is conceivable that their levels of expression are differentially altered in the pathologic versus physiologic models of hypertrophy (Chen et al 2015b). On the other hand, the mitochondrial proteins NADH dehydrogenase (ubiquinone) iron-sulphur protein 4, cytochrome c oxidase subunit 5B and cytochrome b-c1 complex subunit 7 were all upregulated in Δ43 versus A57G hearts.…”

Section: Discussionmentioning

confidence: 99%

Proteomic analysis of physiological versus pathological cardiac remodeling in animal models expressing mutations in myosin essential light chains

Gomes

Kazmierczak

Cheah

et al. 2015

J Muscle Res Cell Motil

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In this study we aimed to provide an in-depth proteomic analysis of differentially expressed proteins in the hearts of transgenic mouse models of pathological and physiological cardiac hypertrophy using tandem mass tag labeling and liquid chromatography tandem mass spectrometry. The Δ43 mouse model, expressing the 43-amino-acid N-terminally truncated myosin essential light chain (ELC) served as a tool to study the mechanisms of physiological cardiac remodeling, while the pathological hypertrophy was investigated in A57G (Alanine 57 → Glycine) ELC mice. The results showed that 30 proteins were differentially expressed in Δ43 versus A57G hearts as determined by multiple pair comparisons of the mutant versus wild-type (WT) samples with P < 0.05. The A57G hearts showed differential expression of nine mitochondrial proteins involved in metabolic processes compared to four proteins for Δ43 hearts when both mutants were compared to WT hearts. Comparisons between Δ43 and A57G hearts showed an upregulation of three metabolically important mitochondrial proteins but downregulation of nine proteins in Δ43 hearts. The physiological model of cardiac hypertrophy (Δ43) showed no changes in the levels of Ca2+-binding proteins relative to WT, while the pathologic model (A57G) showed the upregulation of three Ca2+-binding proteins, including sarcalumenin. Unique differences in chaperone and fatty acid metabolism proteins were also observed in Δ43 versus A57G hearts. The proteomics data support the results from functional studies performed previously on both animal models of cardiac hypertrophy and suggest that the A57G- and not Δ43- mediated alterations in fatty acid metabolism and Ca2+ homeostasis may contribute to pathological cardiac remodeling in A57G hearts.

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“…At 120 and 180 dpi, the left ventricles were collected, included in OCT Tissue-Tek resin (Sakura, USA), frozen in liquid nitrogen, and stored at -80°C. To analyze heart inflammation, serial sections (5 mm) were obtained using a CM1850 cryostat (Leica, Germany), fixed in cold acetone, and stained with hematoxylin and eosin (H&E) (56). The quantification of total inflammatory cells was performed by evaluating 100 microscopic fields (magnification, ×400) per mouse in a double-blind fashion (53,(57)(58)(59).…”

Section: Histopathological and Histochemical Analysismentioning

confidence: 99%

Physical Exercise Promotes a Reduction in Cardiac Fibrosis in the Chronic Indeterminate Form of Experimental Chagas Disease

et al. 2021

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Chagas disease (CD), caused by the protozoan Trypanosoma cruzi, is a neglected tropical disease and a health problem in Latin America. Etiological treatment has limited effectiveness in chronic CD; thus, new therapeutic strategies are required. The practice of physical exercises has been widely advocated to improve the quality of life of CD patients. The most frequent clinical CD manifestation is the chronic indeterminate form (CIF), and the effect of physical exercises on disease progression remains unknown. Here, in a CIF model, we aimed to evaluate the effect of physical exercises on cardiac histological, parasitological, mitochondrial, and oxidative metabolism, electro and echocardiographic profiles, and immunological features. To establish a CIF model, BALB/c and C57BL/6 mice were infected with 100 and 500 trypomastigotes of the Y T. cruzi strain. At 120 days postinfection (dpi), all mouse groups showed normal PR and corrected QT intervals and QRS complexes. Compared to BALB/c mice, C57BL/6 mice showed a lower parasitemia peak, mortality rate, and less intense myocarditis. Thus, C57BL/6 mice infected with 500 parasites were used for subsequent analyses. At 120 dpi, a decrease in cardiac mitochondrial oxygen consumption and an increase in reactive oxygen species (ROS) were detected. When we increased the number of analyzed mice, a reduced heart rate and slightly prolonged corrected QT intervals were detected, at 120 and 150 dpi, which were then normalized at 180 dpi, thus characterizing the CIF. Y-infected mice were subjected to an exercise program on a treadmill for 4 weeks (from 150 to 180 dpi), five times per week in a 30–60-min daily training session. At 180 dpi, no alterations were detected in cardiac mitochondrial and oxidative metabolism, which were not affected by physical exercises, although ROS production increased. At 120 and 180 dpi, comparing infected and non-infected mice, no differences were observed in the levels of plasma cytokines, indicating that a crucial biomarker of the systemic inflammatory profile was absent and not affected by exercise. Compared with sedentary mice, trained Y-infected mice showed similar parasite loads and inflammatory cells but reduced cardiac fibrosis. Therefore, our data show that physical exercises promote beneficial changes that may prevent CD progression.

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Neonatal Death and Heart Failure in Mouse with Transgenic HSP60 Expression

Cited by 8 publications

References 39 publications

Hypertrophic adipocyte-derived exosomal miR-802-5p contributes to insulin resistance in cardiac myocytes through targeting HSP60

Hypertrophic adipocyte-derived exosomal miR-802-5p contributes to insulin resistance in cardiac myocytes through targeting HSP60

Proteomic analysis of physiological versus pathological cardiac remodeling in animal models expressing mutations in myosin essential light chains

Physical Exercise Promotes a Reduction in Cardiac Fibrosis in the Chronic Indeterminate Form of Experimental Chagas Disease

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