Deletion of heat shock protein 60 in adult mouse cardiomyocytes perturbs mitochondrial protein homeostasis and causes heart failure

Fan, Feifei; Duan, Yaoyun; Yang, Feili Lo; Trexler, Christa; Wang, Hong; Huang, Lei; Li, Yali; Tang, Huayuan; Wang, Gang; Fang, Xi; Liu, Jie; Jia, Nan; Chen, Ju; Ouyang, Kunfu

doi:10.1038/s41418-019-0374-x

“…These findings are consistent with previous study showing that knockdown of HSP60 in adult mouse hearts upregulates ROS production and increases CHOP mRNA levels at age of 9 weeks and 11 weeks [51], suggesting an impairment of mitochondrial function. It is well-known that excessive or prolonged UPR activation and ROS accumulation can trigger JNK/IRS-1 signaling pathway leading to insulin resistance [30,31].…”

Section: Discussionsupporting

confidence: 93%

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

Wen

¹

,

Li

²

,

Fu

³

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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“…3b). This finding is consistent with previous study showing that the deletion of HSP60 in adult cardiomyocytes results in the impairment of structure and function of cardiac muscle cells [44]. Furthermore, adiponectin administration markedly inhibited HGinduced apoptosis in siRNA control cells (Fig.…”

Section: Hsp60 Knockdown Mitigated the Protective Effects Of Adiponecsupporting

confidence: 93%

Heat shock protein 60 (HSP60) modulates adiponectin signaling by stabilizing adiponectin receptor

Zhang

¹

,

Liu

²

,

Zhang

³

et al. 2020

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Adiponectin, an adipokine produced and secreted by adipocytes, is involved in regulating the development and progression of insulin resistance, diabetes, and diabetic complications. Heat shock protein 60 (HSP60) is a molecular chaperone, most commonly presenting in mitochondria and participating in the maintenance of protein homeostasis. Accumulating studies have demonstrated that the elevated circulating HSP60 and the decreased intracellular HSP60 are closely associated with diabetic complications such as diabetic cardiomyopathy. However, the underlying mechanism remains poorly understood. In the present study, we reported that HSP60 interacted directly with adiponectin receptors. Its abundance was positively associated with adiponectin action. Furthermore, HSP60 depletion markedly mitigated the protective impacts of adiponectin on high glucose-induced oxidative stress and cell apoptosis in rat cardiac H9c2 cells. In addition, HSP60 knockdown significantly enhanced proteasome activity leading to the degradation of adiponectin receptor 1. Taken together, we showed for the first time that HSP60 interacted with adiponectin receptors and mediated adiponectin signaling through stabilizing adiponectin receptor. This in vitro study also provides an alternative explanation for mechanism by which adiponectin exerts its action.

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“…3b). This finding is consistent with previous study showing that the deletion of HSP60 in adult cardiomyocytes results in the impairment of structure and function of cardiac muscle cells [44]. Furthermore, adiponectin administration markedly inhibited HG-induced apoptosis in siRNA control cells (Fig.…”

Section: Hsp60 Knockdown Mitigated the Protective Effects Of Adiponecsupporting

confidence: 93%

Heat shock protein 60 (HSP60) modulates adiponectin signaling by stabilizing adiponectin receptor

Zhang

¹

,

Liu

²

,

Zhang

³

et al. 2020

Preprint

0

View full text Add to dashboard Cite

Adiponectin, an adipokine produced and secreted by adipocytes, is involved in regulating the development and progression of insulin resistance, diabetes, and diabetic complications. Heat shock protein 60 (HSP60) is a molecular chaperone, most commonly presenting in mitochondria and participating in the maintenance of protein homeostasis. Accumulating studies have demonstrated that the elevated circulating HSP60 and the decreased intracellular HSP60 are closely associated with diabetic complications such as diabetic cardiomyopathy. However, the underlying mechanism remains poorly understood. In the present study, we reported that HSP60 interacted directly with adiponectin receptors. Its abundance was positively associated with adiponectin action. Furthermore, HSP60 depletion markedly mitigated the protective impacts of adiponectin on high glucose-induced oxidative stress and cell apoptosis in rat cardiac H9c2 cells. In addition, HSP60 knockdown significantly enhanced proteasome activity leading to the degradation of adiponectin receptor 1. Taken together, we showed for the first time that HSP60 interacted with adiponectin receptors and mediated adiponectin signaling through stabilizing adiponectin receptor. This in vitro study also provides an alternative explanation for mechanism by which adiponectin exerts its action.

show abstract

Deletion of heat shock protein 60 in adult mouse cardiomyocytes perturbs mitochondrial protein homeostasis and causes heart failure

Cited by 87 publications

References 51 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

Heat shock protein 60 (HSP60) modulates adiponectin signaling by stabilizing adiponectin receptor

Heat shock protein 60 (HSP60) modulates adiponectin signaling by stabilizing adiponectin receptor

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