PPARα agonist prevented the apoptosis induced by glucose and fatty acid in neonatal cardiomyocytes

Nan, Wenlong; Shan, Ti‐Dong; Xiao, Qian; Wu, Ping; Guo, Bing; Ying, Linlin

doi:10.1007/bf03347084

Cited by 19 publications

(11 citation statements)

References 19 publications

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“…We and others have reported that HG induces oxidative stress and apoptosis in cardiomyocytes (Guleria et al, 2011; Rajamani and Essop, 2010; Yu et al, 2010). Previous studies have shown that activation of NF-κB signaling is involved in HG-induced cell apoptosis (Ho et al, 2006; Kuo et al, 2011; Nan et al, 2011), and we have shown similar findings in HG-stimulated cardiomyocytes. Inhibition of the nuclear translocation of NF-κB prevented HG-induced activation of apoptotic signaling and the gene expression of IL-6, TNF-α and MCP-1.…”

Section: Discussionsupporting

confidence: 90%

Retinoic acid protects cardiomyocytes from high glucose‐induced apoptosis through inhibition of NF‐κB signaling Pathway

Nizamutdinova

Guleria

Singh

et al. 2012

Journal Cellular Physiology

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We have previously shown that retinoic acid (RA) has protective effects on high glucose (HG)-induced cardiomyocyte apoptosis. To further elucidate the molecular mechanisms of RA effects, we determined the interaction between nuclear factor (NF)-κB and RA signaling. HG induced a sustained phosphorylation of IKK/IκBα and transcriptional activation of NF-κB in cardiomyocytes. Activated NF-κB signaling has an important role in HG-induced cardiomyocyte apoptosis and gene expression of interleukin-6 (IL-6), tumor necrosis factor (TNF)-α and monocyte chemoattractant protein-1 (MCP-1). All-trans RA (ATRA) and LGD1069, through activation of RAR/RXR-mediated signaling, inhibited the HG-mediated effects in cardiomyocytes. The inhibitory effect of RA on NF-κB activation was mediated through inhibition of IKK/IκBα phosphorylation. ATRA and LGD1069 treatment promoted protein phosphatase 2A (PP2A) activity, which was significantly suppressed by HG stimulation. The RA effects on IKK and IκBα were blocked by okadaic acid or silencing the expression of PP2Ac-subunit, indicating that the inhibitory effect of RA on NF-κB is regulated through activation of PP2A and subsequent dephosphorylation of IKK/IκBα. Moreover, ATRA and LGD1069 reversed the decreased PP2A activity and inhibited the activation of IKK/IκBα and gene expression of MCP-1, IL-6 and TNF-α in the hearts of Zucker diabetic fatty rats. In summary, our findings suggest that the suppressed activation of PP2A contributed to sustained activation of NF-κB in HG-stimulated cardiomyocytes; and that the protective effect of RA on hyperglycemia-induced cardiomyocyte apoptosis and inflammatory responses is partially regulated through activation of PP2A and suppression of NF-κB-mediated signaling and downstream targets.

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Section: Discussionsupporting

confidence: 90%

Retinoic acid protects cardiomyocytes from high glucose‐induced apoptosis through inhibition of NF‐κB signaling Pathway

Nizamutdinova

Guleria

Singh

et al. 2012

Journal Cellular Physiology

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“…In previous studies, we found that PPAR α could inhibit NF- κ B (a protein complex that is involved in cellular responses to stimuli such as stress, cytokines, free radicals, ultraviolet irradiation, oxidized LDL and chronic inflammation). NF- κ B plays a key role in regulating the immune response to chronic inflammatory conditions such as diabetes, and it can directly interact with PPAR α to inhibit fatty acid oxidation and oxidative stress, protecting cardiomyocytes from apoptosis [ 11 ]. However, the upstream signaling pathway has not been elucidated.…”

Section: Discussionmentioning

confidence: 99%

“…The samples were then incubated with anti-HRP antibody for 15 min, washed with PBS, and stained with DAB. The samples were observed and photographed at 400x on a light microscope, and the apoptosis rate was calculated as previously described [ 11 ].…”

Section: Methodsmentioning

confidence: 99%

Exenatide Activates the APPL1-AMPK-PPARαAxis to Prevent Diabetic Cardiomyocyte Apoptosis

Lei

XiaGuang

et al. 2016

Journal of Diabetes Research

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Objective. To investigate the effect and mechanism of the exenatide on diabetic cardiomyopathy. Methods. Rats were divided into control group, diabetes group (D), diabetes treated with insulin (DI) group, and diabetes treat with exenatide (DE) group. We detected apoptosis rate by TUNEL, the adiponectin and high molecular weight adiponectin (HMW-adiponectin) by ELISA, and the expression of APPL1, p-AMPK/T-AMPK, PPARα, and NF-κB by immunohistochemistry and western blotting. Results. Compared with the D group, the apoptosis in the Control and DE groups was decreased (P < 0.05); the adiponectin and HMW-adiponectin were increased (P < 0.05); the APPL1, p-AMPK/T-AMPK, PPARα, and LV −dP/dt were increased (P < 0.05); and the NF-κB, GRP78, and LVEDP were decreased (P < 0.05). Compared with DE group, the glucose levels in the DI group were similar (P < 0.05); the apoptosis and LVEDP were increased; the APPL1, p-AMPK/T-AMPK, PPARα, and LV −dP/dt were decreased (P < 0.05); the NF-κB and GRP78 were increased (P < 0.05); the adiponectin and HMW-adiponectin were significantly decreased (P < 0.05). Conclusion. Our model of diabetic cardiomyopathy was constructed successfully. After being treated with exenatide, the adiponectin and HMW-adiponectin and the APPL1-AMPK-PPARα axis were increased, the NF-κB and the apoptosis were decreased, the cardiac function of the diabetic rats was improved, and these effects were independent of glucose control.

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“…Myocardial inflammation is implicated in the development of DCM (128–131). Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), a primary regulator of inflammatory responses, is activated in the heart upon exposure to FAs or glucose (132, 133). NF-κB induces not only the expression of pro-inflammatory cytokines, such as tumor necrosis factor alpha (TNFα), interleukin 6 (IL6), pro-IL1β, and pro-IL18, but it also induces the expression of NLR family pyrin domain-containing 3 (NLRP3) inflammasome (134).…”

Section: Inflammation Innate and Adaptive Immune Responsesmentioning

confidence: 99%

Diabetic Cardiomyopathy: An Immunometabolic Perspective

et al. 2017

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The heart possesses a remarkable inherent capability to adapt itself to a wide array of genetic and extrinsic factors to maintain contractile function. Failure to sustain its compensatory responses results in cardiac dysfunction, leading to cardiomyopathy. Diabetic cardiomyopathy (DCM) is characterized by left ventricular hypertrophy and reduced diastolic function, with or without concurrent systolic dysfunction in the absence of hypertension and coronary artery disease. Changes in substrate metabolism, oxidative stress, endoplasmic reticulum stress, formation of extracellular matrix proteins, and advanced glycation end products constitute the early stage in DCM. These early events are followed by steatosis (accumulation of lipid droplets) in cardiomyocytes, which is followed by apoptosis, changes in immune responses with a consequent increase in fibrosis, remodeling of cardiomyocytes, and the resultant decrease in cardiac function. The heart is an omnivore, metabolically flexible, and consumes the highest amount of ATP in the body. Altered myocardial substrate and energy metabolism initiate the development of DCM. Diabetic hearts shift away from the utilization of glucose, rely almost completely on fatty acids (FAs) as the energy source, and become metabolically inflexible. Oxidation of FAs is metabolically inefficient as it consumes more energy. In addition to metabolic inflexibility and energy inefficiency, the diabetic heart suffers from impaired calcium handling with consequent alteration of relaxation–contraction dynamics leading to diastolic and systolic dysfunction. Sarcoplasmic reticulum (SR) plays a key role in excitation–contraction coupling as Ca2+ is transported into the SR by the SERCA2a (sarcoplasmic/endoplasmic reticulum calcium-ATPase 2a) during cardiac relaxation. Diabetic cardiomyocytes display decreased SERCA2a activity and leaky Ca2+ release channel resulting in reduced SR calcium load. The diabetic heart also suffers from marked downregulation of novel cardioprotective microRNAs (miRNAs) discovered recently. Since immune responses and substrate energy metabolism are critically altered in diabetes, the present review will focus on immunometabolism and miRNAs.

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PPARα agonist prevented the apoptosis induced by glucose and fatty acid in neonatal cardiomyocytes

Cited by 19 publications

References 19 publications

Retinoic acid protects cardiomyocytes from high glucose‐induced apoptosis through inhibition of NF‐κB signaling Pathway

Retinoic acid protects cardiomyocytes from high glucose‐induced apoptosis through inhibition of NF‐κB signaling Pathway

Exenatide Activates the APPL1-AMPK-PPARαAxis to Prevent Diabetic Cardiomyocyte Apoptosis

Diabetic Cardiomyopathy: An Immunometabolic Perspective

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