β-AR Blockers Suppresses ER Stress in Cardiac Hypertrophy and Heart Failure

Ni, Li; Zhou, Changqing; Duan, Qing; Lv, Jiagao; Fu, Xiangning; Xia, Yong; Wang, Dao Wen

doi:10.1371/journal.pone.0027294

Cited by 75 publications

(66 citation statements)

References 40 publications

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“…Similar to previous reports (Okada et al, 2004;Fu et al, 2010;Ni et al, 2011), ER stress and its associated apoptosis signaling pathways were a common occurrence in failing human hearts. Importantly, the expression of SERCA2a protein was significantly decreased in failing human hearts, which is consistent with previous studies (Meyer et al, 1995;Zarain-Herzberg et al, 1996;Minamisawa et al, 1999).…”

Section: Resultssupporting

confidence: 90%

“…We found that the levels of ER stress and associated apoptosis were significantly increased in hearts of mice treated with ISO or AngII, as well as in cardiac tissue from patients with heart failure. Consistent with previous studies, our data suggest that ER stress-initiated apoptosis plays an important role in cardiomyocyte apoptosis in failing hearts (Okada et al, 2004;Fu et al, 2010;Ni et al, 2011). CYP2J2 expression significantly reduced ER stress and associated apoptosis and attenuated the development of heart failure in vivo.…”

Section: Discussionsupporting

confidence: 92%

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CYP2J2-Derived Epoxyeicosatrienoic Acids Suppress Endoplasmic Reticulum Stress in Heart Failure

Wang

Yang

et al. 2013

Mol Pharmacol

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Prolonged endoplasmic reticulum (ER) stress causes apoptosis and is associated with heart failure. Whether CYP2J2 and its arachidonic acid metabolites [epoxyeicosatrienoic acids (EETs)] have a protective influence on ER stress and heart failure has not been studied. Assays of myocardial samples from patients with end-stage heart failure showed evidence of ER stress. Chronic infusion of isoproterenol (ISO) or angiotensin II (AngII) by osmotic mini-pump induced cardiac hypertrophy and heart failure in mice as evaluated by hemodynamic measurements and echocardiography. Interestingly, transgenic (Tr) mice with cardiomyocyte-specific CYP2J2 expression were protected against heart failure compared with wild-type mice. ISO or AngII administration induced ER stress and apoptosis, and increased levels of intracellular Ca 21 . These phenotypes were abolished by CYP2J2 overexpression in vivo or exogenous EETs treatment of cardiomyocytes in vitro. ISO or AngII reduced sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA2a) expression in hearts or isolated cardiomyocytes; however, loss of SERCA2a expression was prevented in CYP2J2 Tr hearts in vivo or in cardiomyocytes treated with EETs in vitro. The reduction of SERCA2a activity was concomitant with increased oxidation of SERCA2a. EETs reversed SERCA2a oxidation through increased expression of antioxidant enzymes and reduced reactive oxygen species levels. Tempol, a membrane-permeable radical scavenger, similarly decreased oxidized SERCA2a levels, restored SERCA2a activity, and markedly reduced ER stress response in the mice treated with ISO. In conclusion, CYP2J2-derived EETs suppress ER stress response in the heart and protect against cardiac failure by maintaining intracellular Ca 21 homeostasis and SERCA2a expression and activity.

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Section: Resultssupporting

confidence: 90%

Section: Discussionsupporting

confidence: 92%

CYP2J2-Derived Epoxyeicosatrienoic Acids Suppress Endoplasmic Reticulum Stress in Heart Failure

Wang

Yang

et al. 2013

Mol Pharmacol

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“…After confi rming the normal distribution using the Kolmogorov-Smirnov test, statistical differences were evaluated by ANOVA followed by Bonferroni's multiple comparison test ( 28 ). P < 0.05 was accepted as statistically signifi cant.…”

Section: Discussionmentioning

confidence: 99%

CYP2J2 overexpression increases EETs and protects against angiotensin II-induced abdominal aortic aneurysm in mice

Cai

Zhao

Yan

et al. 2013

Journal of Lipid Research

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Abdominal aortic aneurysms (AAAs) mostly occur in humans over 65 years old ( 1, 2 ). The most dreaded complication of AAA is rupture, and it is the 13th leading cause of death in the United States ( 1 ). At the present time, there is no effi cacious pharmacological therapy, and the surgical treatments carry a high mortality ( 2 ). In the past decades, many studies supported the view that infl ammation played an essential role in the pathogenesis of the disease ( 2-4 ).Cytochrome P450 epoxygenase 2J2 (CYP2J2), which is of human origin and mainly expressed in the cardiovascular system, metabolizes arachidonic acids to epoxyeicosatrienoic acids (EETs) ( 5 ). EETs possess diverse biological functions, and observations reveal that EETs exert protective effects on various cardiovascular diseases, including attenuation of heart injuries and anti-hypertension ( 6-13 ). Recently, Zhang et al. ( 5,14 ) reported that administration of soluble epoxide hydrolase (s-EH) inhibitor, which prevents EET hydration, could prevent angiotensin (Ang) II-induced AAA in mice. However, the underlying mechanisms by which EETs exert the effect and whether increased circulation of EETs by CYP2J2 overexpression could prevent AAA formation remain unknown .EETs are the ligands of peroxisome proliferator-activated receptor (PPAR) ␥ and exert anti-infl ammatory effects ( 15 ). Jones et al. ( 16 ) recently reported that activation of PPAR ␥ byAbstract Cytochrome P450 epoxygenase 2J2 (CYP2J2) metabolizes arachidonic acids to form epoxyeicosatrienoic acids (EETs), which possess various benefi cial effects on the cardiovascular system. However, whether increasing EETs production by CYP2J2 overexpression in vivo could prevent abdominal aortic aneurysm (AAA) remains unknown. Here we investigated the effects of recombinant adeno-associated virus (rAAV)-mediated CYP2J2 overexpression on angiotensin (Ang) II-induced AAA in apoE-defi cient mice. rAAV-CYP2J2 delivery led to an abundant aortic CYP2J2 expression and increased EETs generation. It was shown that CYP2J2 overexpression attenuated matrix metalloproteinase expression and activity, elastin degradation, and AAA formation, which was associated with reduced aortic infl ammation and macrophage infi ltration. In cultured vascular smooth muscle cells (VSMCs), rAAVmediated CYP2J2 overexpression and EETs markedly suppressed Ang II-induced infl ammatory cytokine expression. Moreover, overexpressed CYP2J2 and EETs inhibited Ang II-induced macrophage migration in a VSMC-macrophage coculture system. We further indicated that these protective effects were mediated by peroxisome proliferatoractivated receptor (PPAR) ␥ activation. Taken together, these results provide evidence that rAAV-mediated CYP2J2 overexpression prevents AAA development which is likely via PPAR ␥ activation and anti-infl ammatory action, suggesting that increasing EETs levels could be considered as a potential strategy to prevent and treat AAA. 25 February 2013. Published, JLR Papers in Press, February 26, 2013 DOI 10.1194 , apoE-defi ci...

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“…ATF4 is thought to play a dominant role in inducing CHOP expression in response to ERS because the expression of ATF4 is upregulated when eIF2α is phosphorylated by PERK [41] . Overexpression of CHOP promotes apoptosis in several cell lines, whereas CHOP-deficient cells are resistant to ERS-induced apoptosis [42] . CHOP leads to upregulation of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptors and thus promotes the extrinsic apoptotic pathway [43,44] .…”

Section: Endoplasmic Reticulum Stress Promotes Er Homeostasis Via Thementioning

confidence: 99%

“…However, the mechanisms underlying the therapeutic effects of β-AR blockers on failing hearts is poorly understood. Zhou et al [42] found that metoprolol and propranolol suppressed ERS and ERS-mediated apoptosis by decreasing the expression of ERS chaperones GRP78, XBP-1, and calmodulin kinase II (CaMKII) and apoptosis maker CHOP in hypertrophic and failing hearts of rats. Metoprolol also normalized the level of calcium and decreased the expression of p-eIF2α in dogs with heart failure [138] .…”

Section: Endoplasmic Reticulum Stress Is Involved In the Development mentioning

confidence: 99%

Endoplasmic reticulum stress: a novel mechanism and therapeutic target for cardiovascular diseases

2016

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Endoplasmic reticulum is a principal organelle responsible for folding, post-translational modifications and transport of secretory, luminal and membrane proteins, thus palys an important rale in maintaining cellular homeostasis. Endoplasmic reticulum stress (ERS) is a condition that is accelerated by accumulation of unfolded/misfolded proteins after endoplasmic reticulum environment disturbance, triggered by a variety of physiological and pathological factors, such as nutrient deprivation, altered glycosylation, calcium depletion, oxidative stress, DNA damage and energy disturbance, etc. ERS may initiate the unfolded protein response (UPR) to restore cellular homeostasis or lead to apoptosis. Numerous studies have clarified the link between ERS and cardiovascular diseases. This review focuses on ERS-associated molecular mechanisms that participate in physiological and pathophysiological processes of heart and blood vessels. In addition, a number of drugs that regulate ERS was introduced, which may be used to treat cardiovascular diseases. This review may open new avenues for studying the pathogenesis of cardiovascular diseases and discovering novel drugs targeting ERS.

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β-AR Blockers Suppresses ER Stress in Cardiac Hypertrophy and Heart Failure

Cited by 75 publications

References 40 publications

CYP2J2-Derived Epoxyeicosatrienoic Acids Suppress Endoplasmic Reticulum Stress in Heart Failure

CYP2J2-Derived Epoxyeicosatrienoic Acids Suppress Endoplasmic Reticulum Stress in Heart Failure

CYP2J2 overexpression increases EETs and protects against angiotensin II-induced abdominal aortic aneurysm in mice

Endoplasmic reticulum stress: a novel mechanism and therapeutic target for cardiovascular diseases

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