Fenofibrate increases cardiac autophagy via FGF21/SIRT1 and prevents fibrosis and inflammation in the hearts of Type 1 diabetic mice

Zhang, Jingjing; Cheng, Yiyun; Gu, Junlian; Wang, Shudong; Zhou, Shanshan; Wang, Yuehui; Tan, Yi; Feng, Wenke; Fu, Yue; Mellen, Nicholas; Cheng, Rui; Ma, Jian-Xing; Zhang, Chi; Li, Zhanquan; Cai, Lu

doi:10.1042/cs20150623

Cited by 131 publications

(92 citation statements)

References 58 publications

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“…Many studies suggest that HDAC inhibitors protect the heart against MI [91], I/R injury [92], and spontaneous hypertension [93]. Recently, HDAC inhibition has been reported to effectively attenuate DCM [94,95,96], which indicates that the HDAC might be a potential target of DCM. Interestingly, Majumdar et al found that expression of phosphorylated ERK1/2, but not total ERK1/2, in H9c2 cells was significantly decreased by exposure to trichostatin A (TSA), an HDAC inhibitor, for 4–24 h [97].…”

Section: Hdac Inhibitors Regulate Erk1/2 Activity In the Heartmentioning

confidence: 99%

The Role of ERK1/2 in the Development of Diabetic Cardiomyopathy

Sun

Tong

et al. 2016

IJMS

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Diabetes mellitus is a chronic metabolic condition that affects carbohydrate, lipid and protein metabolism and may impair numerous organs and functions of the organism. Cardiac dysfunction afflicts many patients who experience the oxidative stress of the heart. Diabetic cardiomyopathy (DCM) is one of the major complications that accounts for more than half of diabetes-related morbidity and mortality cases. Chronic hyperglycemia and hyperlipidemia from diabetes mellitus cause cardiac oxidative stress, endothelial dysfunction, impaired cellular calcium handling, mitochondrial dysfunction, metabolic disturbances, and remodeling of the extracellular matrix, which ultimately lead to DCM. Although many studies have explored the mechanisms leading to DCM, the pathophysiology of DCM has not yet been fully clarified. In fact, as a potential mechanism, the associations between DCM development and mitogen-activated protein kinase (MAPK) activation have been the subjects of tremendous interest. Nonetheless, much remains to be investigated, such as tissue- and cell-specific processes of selection of MAPK activation between pro-apoptotic vs. pro-survival fate, as well as their relation with the pathogenesis of diabetes and associated complications. In general, it turns out that MAPK signaling pathways, such as extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun N-terminal protein kinase (JNK) and p38 MAP kinase, are demonstrated to be actively involved in myocardial dysfunction, hypertrophy, fibrosis and heart failure. As one of MAPK family members, the activation of ERK1/2 has also been known to be involved in cardiac hypertrophy and dysfunction. However, many recent studies have demonstrated that ERK1/2 signaling activation also plays a crucial role in FGF21 signaling and exerts a protective environment of glucose and lipid metabolism, therefore preventing abnormal healing and cardiac dysfunction. The duration, extent, and subcellular compartment of ERK1/2 activation are vital to differential biological effects of ERK1/2. Moreover, many intracellular events, including mitochondrial signaling and protein kinases, manipulate signaling upstream and downstream of MAPK, to influence myocardial survival or death. In this review, we will summarize the roles of ERK1/2 pathways in DCM development by the evidence from current studies and will present novel opinions on “differential influence of ERK1/2 action in cardiac dysfunction, and protection against myocardial ischemia-reperfusion injury”.

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Section: Hdac Inhibitors Regulate Erk1/2 Activity In the Heartmentioning

confidence: 99%

The Role of ERK1/2 in the Development of Diabetic Cardiomyopathy

Sun

Tong

et al. 2016

IJMS

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“…Diabetes is strongly associated with systemic cardiovascular disease [2,3,12,13,14,15] but the relationship with pulmonary vascular disease has often been disregarded [16]. Pulmonary complications, while often subclinical in diabetic patients because of the lungs’ functional reserve, may become clinically important as patients subsequently develop chronic restrictive and obstructive pulmonary functional changes.…”

Section: Diabetic Lung Fibrosismentioning

confidence: 99%

Diabetic Microvascular Disease and Pulmonary Fibrosis: The Contribution of Platelets and Systemic Inflammation

Jagadapillai

Rane

Lin

et al. 2016

IJMS

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Diabetes is strongly associated with systemic inflammation and oxidative stress, but its effect on pulmonary vascular disease and lung function has often been disregarded. Several studies identified restrictive lung disease and fibrotic changes in diabetic patients and in animal models of diabetes. While microvascular dysfunction is a well-known complication of diabetes, the mechanisms leading to diabetes-induced lung injury have largely been disregarded. We described the potential involvement of diabetes-induced platelet-endothelial interactions in perpetuating vascular inflammation and oxidative injury leading to fibrotic changes in the lung. Changes in nitric oxide synthase (NOS) activation and decreased NO bioavailability in the diabetic lung increase platelet activation and vascular injury and may account for platelet hyperreactivity reported in diabetic patients. Additionally, the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway has been reported to mediate pancreatic islet damage, and is implicated in the onset of diabetes, inflammation and vascular injury. Many growth factors and diabetes-induced agonists act via the JAK/STAT pathway. Other studies reported the contribution of the JAK/STAT pathway to the regulation of the pulmonary fibrotic process but the role of this pathway in the development of diabetic lung fibrosis has not been considered. These observations may open new therapeutic perspectives for modulating multiple pathways to mitigate diabetes onset or its pulmonary consequences.

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“…17 A previous study has shown that SIRT-1 expression is significantly decreased in DM. 18 Moreover, NFkB also generally works with other transcription factors such as nuclear factor (erythroid derived 2)-like 2 (Nrf2). 19 Under oxidative stress conditions including DM, Nrf2 modulates its downstream antioxidant defense enzymes such as superoxide dismutase (SOD), heme oxygenase-1 (HO-1), NAD(P)H dehydrogenase quinone 1 (NQO1), catalase, and glutathione peroxidase (GPx), which remove excessive ROS.…”

Section: Introductionmentioning

confidence: 99%

Gamma-tocopherol supplementation ameliorated hyper-inflammatory response during the early cutaneous wound healing in alloxan-induced diabetic mice

Shin

Yang

Lim

2016

Exp Biol Med (Maywood)

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Gamma tocopherol has shown ameliorative effect on diabetic wound healing by regulation of inflammation, oxidative stress, and apoptosis demonstrated by nuclear factor kappa B, nuclear factor (erythroid derived 2)-like 2, and sirtuin-1. AbstractDelayed wound healing is one of the major diabetic complications. During wound healing process, the early inflammatory stage is important for better prognosis. One of antioxidant nutrient, gamma-tocopherol (GT) is considered to regulate inflammatory conditions. This study investigated the effect of GT supplementation on mechanism associated with inflammation, oxidative stress, and apoptosis during early cutaneous wound healing in diabetic mice. Diabetes was induced by alloxan injection in ICR mice. All mice were divided into three groups: non-diabetic control mice (CON), diabetic control mice (DMC), and diabetic mice supplemented with GT (GT). After two weeks of GT supplementation, excisional wounds were made by biopsy punches (4 mm). Diabetic mice showed increases in fasting blood glucose (FBG) level, hyper-inflammatory response, oxidative stress, and delayed wound closure rate compared to non-diabetic mice. However, GT supplementation reduced FBG level and accelerated wound closure rate by regulation of inflammatory response-related proteins such as nuclear factor kappa B, interleukin-1b, tumor necrosis factor-a, and c-reactive protein, and oxidative stress-related markers including nuclear factor (erythroid derived 2)-like 2, NAD(P)H dehydrogenase quinone1, heme oxygenase-1, manganese superoxide dismutase, catalase and glutathione peroxidase and apoptosis-related markers such as sirtuin-1, peroxisome proliferator-activated receptor gamma coactivator 1-, and p53 in diabetic mice. Taken together, GT would be a potential therapeutic to prevent diabetes-induced delayed wound healing by regulation of inflammatory response, apoptosis, and oxidative stress.

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Fenofibrate increases cardiac autophagy via FGF21/SIRT1 and prevents fibrosis and inflammation in the hearts of Type 1 diabetic mice

Cited by 131 publications

References 58 publications

The Role of ERK1/2 in the Development of Diabetic Cardiomyopathy

The Role of ERK1/2 in the Development of Diabetic Cardiomyopathy

Diabetic Microvascular Disease and Pulmonary Fibrosis: The Contribution of Platelets and Systemic Inflammation

Gamma-tocopherol supplementation ameliorated hyper-inflammatory response during the early cutaneous wound healing in alloxan-induced diabetic mice

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