Endoplasmic reticulum stress induces cardiac dysfunction through architectural modifications and alteration of mitochondrial function in cardiomyocytes

Prola, Alexandre; Nichtová, Zuzana; Silva, Julie Pires Da; Piquereau, Jérôme; Monceaux, Kévin; Guilbert, Arnaud; Gressette, Mélanie; Ventura‐Clapier, Renée; Garnier, Anne; Zahradnı́k, Ivan; Novotová, Marta; Lemaire, Christophe

doi:10.1093/cvr/cvy197

Cited by 35 publications

(29 citation statements)

References 45 publications

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“…These data are also in agreement with the results obtained in animal models of T2DM (34). Interestingly, induction of ER stress by tunicamycin can also induce profound mitochondrial remodeling, including decreased ability to process fatty acids (16). Whether ER stress is the initiator, or works concomitantly with other disturbances (e.g., fatty acid overload of cardiomyocytes) leading to the downward spiral of adverse mitochondrial remodeling in human diabetic myocardium, remains to be investigated.…”

Section: Er Stress and Apoptosis In Diabetic Myocardiumsupporting

confidence: 88%

“…Quantitative RT-PCR of total ventricular RNA was performed as previously described (16). mRNA levels for all target genes (PPARa [peroxisome proliferator-activated receptor a], FAT/CD36 [fatty acid translocase/cluster of differentiation 36], and CPT1 [carnitine palmitoyltransferase 1]) were normalized to Ywhaz and PolR2A levels.…”

Section: Rna Isolation and Quantitative Rt-pcrmentioning

confidence: 99%

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Disturbed Fatty Acid Oxidation, Endoplasmic Reticulum Stress, and Apoptosis in Left Ventricle of Patients With Type 2 Diabetes

et al. 2019

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Chronic heart failure is a common complication in patients with type 2 diabetes mellitus (T2DM). T2DM is associated with disturbed metabolism of fat, which can result in excessive accumulation of lipids in cardiac muscle. In the current study, we assessed mitochondrial oxidation of carbohydrates and fatty acids, lipid accumulation, endoplasmic reticulum (ER) stress, and apoptosis in diabetic left ventricle. Left ventricular myocardium from 37 patients (a group of patients with diabetes and a group of patients without diabetes [ejection fraction >50%]) undergoing coronary artery bypass graft surgery was obtained by subepicardial needle biopsy. The group with diabetes had a significantly decreased rate of mitochondrial respiration fueled by palmitoyl-carnitine that correlated with blood glucose dysregulation, while there was no difference in oxidation of pyruvate. Diabetic myocardium also had significantly decreased activity of hydroxyacyl-CoA dehydrogenase (HADHA) and accumulated more lipid droplets and ceramide. Also, markers of ER stress response (GRP78 and CHOP) and apoptosis (cleaved caspase-3) were elevated in diabetic myocardium. These results show that, even in the absence of contractile failure, diabetic heart exhibits a decreased mitochondrial capacity for β-oxidation, increased accumulation of intracellular lipids, ER stress, and greater degree of apoptosis. Lower efficiency of mitochondrial fatty acid oxidation may represent a potential target in combating negative effects of diabetes on the heart.

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Section: Er Stress and Apoptosis In Diabetic Myocardiumsupporting

confidence: 88%

Section: Rna Isolation and Quantitative Rt-pcrmentioning

confidence: 99%

Disturbed Fatty Acid Oxidation, Endoplasmic Reticulum Stress, and Apoptosis in Left Ventricle of Patients With Type 2 Diabetes

et al. 2019

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“…In addition, we found that inhibition of ER stress-induced autophagy by 3-MA or CQ triggers cell death, suggesting that activation of autophagy may counteract cell death and serve as a cardioprotective mechanism against ER stress. The impairment of the mitochondrial function associated with ER stress-induced heart injury ( [34] and Figure 5A) led us to investigate the involvement of mitophagy, a form of autophagy that selectively eliminates damaged mitochondria. By electron microscopy and subcellular fractionation, we demonstrated that autophagic vacuoles can contain damaged mitochondria and that Parkin is translocated to mitochondria under ER stress.…”

Section: Discussionmentioning

confidence: 99%

SIRT1 Protects the Heart from ER Stress-Induced Injury by Promoting eEF2K/eEF2-Dependent Autophagy

Silva

Monceaux

Guilbert

et al. 2020

Cells

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Many recent studies have demonstrated the involvement of endoplasmic reticulum (ER) stress in the development of cardiac diseases and have suggested that modulation of ER stress response could be cardioprotective. Previously, we demonstrated that the deacetylase Sirtuin 1 (SIRT1) attenuates ER stress response and promotes cardiomyocyte survival. Here, we investigated whether and how autophagy plays a role in SIRT1-afforded cardioprotection against ER stress. The results revealed that protective autophagy was initiated before cell death in response to tunicamycin (TN)-induced ER stress in cardiac cells. SIRT1 inhibition decreased ER stress-induced autophagy, whereas its activation enhanced autophagy. In response to TN- or isoproterenol-induced ER stress, mice deficient for SIRT1 exhibited suppressed autophagy along with exacerbated cardiac dysfunction. At the molecular level, we found that in response to ER stress (i) the extinction of eEF2 or its kinase eEF2K not only reduced autophagy but further activated cell death, (ii) inhibition of SIRT1 inhibited the phosphorylation of eEF2, (iii) eIF2α co-immunoprecipitated with eEF2K, and (iv) knockdown of eIF2α reduced the phosphorylation of eEF2. Our results indicate that in response to ER stress, SIRT1 activation promotes cardiomyocyte survival by enhancing autophagy at least through activation of the eEF2K/eEF2 pathway.

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“…In recent years, a growing body of studies has noted that the dysregulated endoplasmic reticulum (ER) stress is a critical positive factor deeply involved in cardiomyocyte apoptosis occurring in cardiovascular diseases including MI, 5‐8 rendering it as a potential therapeutic target in MI 9 . ER stress can induce cardiac dysfunction via architectural modifications and altering mitochondrial function in cardiomyocytes 10 . Lately, the NADPH oxidase, 11 calpain‐1 12 and sestrin2‐mTORC1 signalling 13 have been implicated in ER stress modulation in MI.…”

Section: Introductionmentioning

confidence: 99%

“…9 ER stress can induce cardiac dysfunction via architectural modifications and altering mitochondrial function in cardiomyocytes. 10 Lately, the NADPH oxidase, 11 calpain-1 12 and sestrin2-mTORC1 signalling 13 have been implicated in ER stress modulation in MI. However, how ER stress is regulated is not fully understood.…”

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confidence: 99%

FABP4 inhibitor BMS309403 protects against hypoxia‐induced H9c2 cardiomyocyte apoptosis through attenuating endoplasmic reticulum stress

Sun

et al. 2020

J Cellular Molecular Medi

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Acute myocardial infarction (MI), one of the leading causes of disability and death in the world, 1 is featured by the ischaemia-induced cardiomyocyte loss due to necrosis and apoptosis. 2 To date, increasing evidence has shown that the cardiomyocyte apoptosis spotted in the border zone of infarct lesions and the remote zone of non-infarcted myocardium deteriorates the post-MI remodelling and cardiac dysfunction, together contributing to heart failure development. 3,4 Therefore, advancing the mechanisms of cardiomyocyte apoptosis during the early stage of MI is extremely important for reversing this pathogenic process and ameliorating cardiac function of patients with MI.

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Endoplasmic reticulum stress induces cardiac dysfunction through architectural modifications and alteration of mitochondrial function in cardiomyocytes

Abstract: Our findings show that ER stress induces cytoarchitectural and metabolic alterations in cardiomyocytes and provide evidences that ER stress could represent a primary mechanism that contributes to the impairment of energy metabolism reported in most cardiac diseases.

Cited by 35 publications

References 45 publications

Disturbed Fatty Acid Oxidation, Endoplasmic Reticulum Stress, and Apoptosis in Left Ventricle of Patients With Type 2 Diabetes

Disturbed Fatty Acid Oxidation, Endoplasmic Reticulum Stress, and Apoptosis in Left Ventricle of Patients With Type 2 Diabetes

SIRT1 Protects the Heart from ER Stress-Induced Injury by Promoting eEF2K/eEF2-Dependent Autophagy

FABP4 inhibitor BMS309403 protects against hypoxia‐induced H9c2 cardiomyocyte apoptosis through attenuating endoplasmic reticulum stress

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