Nobiletin, a Polymethoxy Flavonoid, Protects Against Cardiac Hypertrophy Induced by Pressure-Overload via Inhibition of NAPDH Oxidases and Endoplasmic Reticulum Stress

Zhang, Ning; Wei, Wenying; Zheng, Yang; Che, Yan; Jin, Ya‐Ge; Liao, Hai‐Han; Wang, Shasha; Deng, Wei; Tang, Qi‐Zhu

doi:10.1159/000478960

Cited by 37 publications

(31 citation statements)

References 32 publications

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“…In several cell lines, ER stress has been found to be activated following UA exposure [37-39] and was reported to be involved in UA-induced apoptosis in one of these studies [39]. The results of the present study revealed that high levels of UA induced ER stress in cultured cardiomyocytes as well as rat myocardium, as evidenced by the increased GRP78, p-PERK, and CHOP expression, which are widely used as markers of ER stress [40-43]. …”

Section: Discussionmentioning

confidence: 58%

Uric Acid Induces Cardiomyocyte Apoptosis via Activation of Calpain-1 and Endoplasmic Reticulum Stress

Yan

Chen

et al. 2018

Cell Physiol Biochem

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Background/Aims: Hyperuricemia is associated with an increased risk for multiple cardiovascular diseases, but the underlying mechanisms remain largely elusive. Calpain-1 is a protease that is implicated in several pathological conditions that affect the heart. The aim of this current study was to test the effects of uric acid (UA) on cardiomyocyte survival and cardiac function and to investigate the role of calpain-1 in the UA-induced effects in the heart and their underlying mechanisms. Methods: In vivo, hyperuricemia was induced by oxonic acid (OA) administration in Sprague-Dawley rats for 16 weeks; TUNEL staining was used to identify apoptotic cells. Left ventricular (LV) sections were stained with Sirius Red to evaluate interstitial fibrosis. Cardiac catheterization was performed to evaluate cardiac function. In vitro, cultured H9c2 cells were incubated with different UA concentrations. MTT assays and flow cytometry were used to evaluate cell viability and apoptosis. All related gene expression levels were analyzed by quantitative real-time PCR (qRT-PCR), and all protein expression levels were analyzed by western blotting. Results: Hyperuricemia induction in vivo resulted in cellular apoptosis, interstitial fibrosis and diastolic dysfunction in the rat hearts, as well as increased activation of calpain-1 and endoplasmic reticulum (ER) stress, while allopurinol treatment mitigated the above changes. UA administration in vitro increased apoptosis and decreased H9c2 cell viability in a dose-dependent manner. Increased activation of calpain-1 and ER stress was also observed in the groups with high UA levels. Calpain-1 siRNA and the calpain inhibitor CI-III alleviated UA-induced ER stress and apoptosis, while inhibiting ER stress by tauroursodeoxycholic acid (TUDCA) mitigated UA-induced apoptosis without affecting calpain-1 expression or activity. Conclusions: These findings suggest that UA induces cardiomyocyte apoptosis through activation of calpain-1 and ER stress. These results may provide new insights into the mechanisms of hyperuricemia-associated cardiovascular risks and hopefully identify new treatment targets.

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Section: Discussionmentioning

confidence: 58%

Uric Acid Induces Cardiomyocyte Apoptosis via Activation of Calpain-1 and Endoplasmic Reticulum Stress

Yan

Chen

et al. 2018

Cell Physiol Biochem

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“…Besides thermogenesis and the regulation of ATP synthesis, there are two other primary hypotheses regarding the physiological roles of UCP3: the regulation of fatty acid oxidation and the reduction of the mitochondrial generation of ROS [28]. And previous study showed that myocardial hypertrophy was accompanied by increasing of ROS production [29, 30]. The downregulation of UCP3 has previously been reported in hypertrophic myocardium and heart failure [31, 32].…”

Section: Discussionmentioning

confidence: 99%

Atorvastatin Attenuates Myocardial Hypertrophy in Spontaneously Hypertensive Rats via the C/EBPβ/PGC-1α/UCP3 Pathway

Chen¹,

Chang²,

Zhang³

et al. 2018

Cell Physiol Biochem

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Background/Aims: Many clinical and experimental studies have shown that treatment with statins could prevent myocardial hypertrophy and remodeling induced by hypertension and myocardial infarction. But the molecular mechanism was not clear. We aimed to investigate the beneficial effects of atorvastatin on hypertension-induced myocardial hypertrophy and remodeling in spontaneously hypertensive rats (SHR) with the hope of revealing other potential mechanisms or target pathways to interpret the pleiotropic effects of atorvastatin on myocardial hypertrophy. Methods: The male and age-matched animals were randomly divided into three groups: control group (8 WKY), SHR (8 rats) and intervention group (8 SHR). The SHR in intervention group were administered by oral gavage with atorvastatin (suspension in distilled water, 10 mg/Kg once a day) for 6 weeks, and the other two groups were administered by gavage with equal quantity distilled water. Blood pressure of rats was measured every weeks using a standard tail cuff sphygmomanometer. Left ventricular (LV) dimensions were measured from short-axis views of LV under M-mode tracings using Doppler echocardiograph. Cardiomyocyte apoptosis was assessed by the TUNEL assay. The protein expression of C/EBPβ, PGC-1α and UCP3 were detected by immunohistochemistry or Western blot analysis. Results: At the age of 16 weeks, the mean arterial pressure of rats in three groups were 103.6±6.1, 151.8±12.5 and 159.1±6.2 mmHg respectively, and there wasn’t statistically significant difference between the SHR and intervention groups. Staining with Masson’s trichrome demonstrated that the increased interstitial fibrosis of LV and ventricular remodeling in the SHR group were attenuated by atorvastatin treatment. Echocardiography examination exhibited that SHR with atorvastatin treatment showed an LV wall thickness that was obviously lower than that of water-treated SHR. In hypertrophic myocardium, accompanied by increasing C/EBPβ expression and the percentage of TUNEL-positive cells, the expression of Bcl-2/Bax ratio, PGC-1α and UCP3 were reduced, all of which could be abrogated by treatment with atorvastatin for 6 weeks. Conclusion: This study further confirmed that atorvastatin could attenuate myocardial hypertrophy and remodeling in SHR by inhibiting apoptosis and reversing changes in mitochondrial metabolism. The C/EBPβ/PGC-1α/UCP3 signaling pathway might also be important for elucidating the beneficial pleiotropic effects of atorvastatin on myocardial hypertrophy.

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“…However, the exact contributions of NOB in cerebral I/R injury are far from clear, and the potential pathogenesis implicated in ERS-related apoptosis remains completely unknown. An additional study found that NOB could lower myocardial apoptosis in pressure overload-induced cardiac hypertrophy, in which the mechanisms are implied with NOB's ERS-repressing action (13). Intriguingly, a number of investigations have shown the crucial involvement of the phosphoinositide 3-kinase (PI3K) and serine/threonine kinase (AKT) pathway in the multiple bioactivities of NOB as a compelling approach to anticancer effects (14,15).…”

Section: Introductionmentioning

confidence: 99%

Nobiletin protects PC12 cells from ERS‑induced apoptosis in OGD/R injury via activation of the PI3K/AKT pathway

Yang

Zhang

et al. 2018

Exp Ther Med

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Nobiletin (NOB) possesses multiple pharmacological effects, but its anti-apoptotic property has acquired a great deal of attention. Endoplasmic reticulum (ER) stress (ERS)-induced apoptosis acts as the pivotal aetiology in neuronal oxygen-glucose deprivation and reoxygenation (OGD/R) injury. The aim of this study focused on whether NOB exerts neuro-protective effects on OGD/R injury by repressing ERS-induced apoptosis. The PC12 neuronal cell line was subjected to 4 h OGD and 24 h reoxygenation following NOB treatment. A PI3K/AKT inhibitor (LY294002) was added during the mechanistic experiments. Cell viability, lactate dehydrogenase (LDH) release and apoptosis were determined. Western blotting was used to measure protein expression levels. The results showed that OGD/R caused neuronal damageas exhibited by the increase in LDH release and the reduction of cellular viability. Moreover, ERS-induced apoptosis was markedly stimulated by OGD/R in PC12 cells, as evidenced by the elevation in the apoptotic rate and protein levels of C/EBP homologous protein/glucose-regulated protein-78. However, NOB administration significantly reversed neuronal damage and the ERS-induced apoptosis in response to OGD/R injury. Mechanistic detections showed that the neuron-favorable and ERS-repressing contributions of NOB were, in part, a result of the activation of the PI3K/AKT pathway, which was validated by a specific PI3K/AKT inhibitor (LY294002). Therefore, NOB protects PC12 cells from ERS-induced apoptosis in OGD/R injury mainly through enhancement of the PI3K/AKT pathway, which may provide a novel therapeutic avenue for the prevention of cerebral ischemia/reperfusion injury.

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Nobiletin, a Polymethoxy Flavonoid, Protects Against Cardiac Hypertrophy Induced by Pressure-Overload via Inhibition of NAPDH Oxidases and Endoplasmic Reticulum Stress

Cited by 37 publications

References 32 publications

Uric Acid Induces Cardiomyocyte Apoptosis via Activation of Calpain-1 and Endoplasmic Reticulum Stress

Uric Acid Induces Cardiomyocyte Apoptosis via Activation of Calpain-1 and Endoplasmic Reticulum Stress

Atorvastatin Attenuates Myocardial Hypertrophy in Spontaneously Hypertensive Rats via the C/EBPβ/PGC-1α/UCP3 Pathway

Nobiletin protects PC12 cells from ERS‑induced apoptosis in OGD/R injury via activation of the PI3K/AKT pathway

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