PERK/ATF4-dependent expression of the stress response protein REDD1 promotes proinflammatory cytokine expression in the heart of obese mice

Endoplasmic reticulum (ER) stress and inflammation are hallmarks of myocardial impairment. Here we investigated a role for the stress response protein REDD1 as a molecular link between ER stress and inflammation in cardiomyocytes. In mice fed a high-fat high-sucrose (HFHS, 42% kcal fat, 34% sucrose by weight) diet for 12 weeks, REDD1 expression in the heart was increased in coordination with markers of ER stress and inflammation. In human AC16 cardiomyocytes exposed to either hyperglycemic conditions or the saturated fatty acid palmitate, REDD1 expression was increased coincident with ER stress and upregulated expression of the pro-inflammatory cytokines IL-1β, IL-6, and TNF⍺. In cardiomyocytes exposed to hyperglycemic/hyperlipidemic conditions, pharmacological inhibition of the ER kinase PERK or knockdown of the transcription factor ATF4 prevented the increase in REDD1 expression. REDD1 deletion reduced pro-inflammatory cytokine expression in both cardiomyocytes exposed to hyperglycemic/hyperlipidemic conditions and in the hearts of obese mice. Overall, the findings support a model wherein HFHS diet contributes to the development of inflammation in cardiomyocytes by promoting REDD1 expression via activation of a PERK/ATF4 signaling axis.

[1]  Congzhou M. Sha,et al.  Activation of Disulfide Redox Switch in REDD1 Promotes Oxidative Stress Under Hyperglycemic Conditions , 2022, Diabetes.

[2]  Kebin Hu,et al.  REDD1 Ablation Attenuates the Development of Renal Complications in Diabetic Mice , 2022, Diabetes.

[3]  A. Barber,et al.  Müller Glial Expression of REDD1 Is Required for Retinal Neurodegeneration and Visual Dysfunction in Diabetic Mice , 2022, Diabetes.

[4]  Pian-pian Huang,et al.  Redd1 knockdown prevents doxorubicin-induced cardiac senescence , 2021, Aging.

[5]  P. Libby,et al.  Inhibition of Interleukin-1β and Reduction in Atherothrombotic Cardiovascular Events in the CANTOS Trial. , 2020, Journal of the American College of Cardiology.

[6]  A. Barber,et al.  The stress response protein REDD1 promotes diabetes-induced oxidative stress in the retina by Keap1-independent Nrf2 degradation , 2020, The Journal of Biological Chemistry.

[7]  Tao Yu,et al.  REDD1 knockdown protects H9c2 cells against myocardial ischemia/reperfusion injury through Akt/mTORC1/Nrf2 pathway-ameliorated oxidative stress: An in vitro study. , 2019, Biochemical and biophysical research communications.

[8]  A. Arya,et al.  Endoplasmic Reticulum Stress Activates Unfolded Protein Response Signaling and Mediates Inflammation, Obesity, and Cardiac Dysfunction: Therapeutic and Molecular Approach , 2019, Front. Pharmacol..

[9]  Manisha J. Oza,et al.  ER stress response mediates diabetic microvascular complications. , 2019, Drug discovery today.

[10]  C. Lemaire,et al.  Disturbed Fatty Acid Oxidation, Endoplasmic Reticulum Stress, and Apoptosis in Left Ventricle of Patients With Type 2 Diabetes , 2019, Diabetes.

[11]  A. Barber,et al.  REDD1 Activates a ROS-Generating Feedback Loop in the Retina of Diabetic Mice , 2019, Investigative ophthalmology & visual science.

[12]  Xuhui Hou,et al.  Blocking the REDD1/TXNIP axis ameliorates LPS-induced vascular endothelial cell injury through repressing oxidative stress and apoptosis. , 2019, American journal of physiology. Cell physiology.

[13]  A. Roseman,et al.  The structural basis of translational control by eIF2 phosphorylation , 2018, Nature Communications.

[14]  R. Feehan,et al.  Deletion of the stress‐response protein REDD1 promotes ceramide‐induced retinal cell death and JNK activation , 2018, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[15]  T. Psaltopoulou,et al.  Western Dietary Pattern Is Associated With Severe Coronary Artery Disease , 2018, Angiology.

[16]  Yoon Kyung Choi,et al.  REDD‐1 aggravates endotoxin‐induced inflammation VIA atypical NF‐κB activation , 2018, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[17]  A. Barber,et al.  Deletion of the Akt/mTORC1 Repressor REDD1 Prevents Visual Dysfunction in a Rodent Model of Type 1 Diabetes , 2017, Diabetes.

[18]  J. Tanti,et al.  Implication of REDD1 in the activation of inflammatory pathways , 2017, Scientific Reports.

[19]  C. Zhang,et al.  Role of Endoplasmic Reticulum Stress, Autophagy, and Inflammation in Cardiovascular Disease , 2017, Front. Cardiovasc. Med..

[20]  M. Volpe,et al.  An overview of the inflammatory signalling mechanisms in the myocardium underlying the development of diabetic cardiomyopathy. , 2017, Cardiovascular research.

[21]  S. Carbone,et al.  A high-sugar and high-fat diet impairs cardiac systolic and diastolic function in mice. , 2015, International journal of cardiology.

[22]  R. Iqbal,et al.  Major dietary patterns and risk of acute myocardial infarction in young, urban Pakistani population , 2015, Pakistan journal of medical sciences.

[23]  G. Sweeney,et al.  Palmitate Induces ER Stress and Autophagy in H9c2 Cells: Implications for Apoptosis and Adiponectin Resistance , 2015, Journal of cellular physiology.

[24]  P. Fort,et al.  Regulated in Development and DNA Damage 1 Is Necessary for Hyperglycemia-induced Vascular Endothelial Growth Factor Expression in the Retina of Diabetic Rodents* , 2014, The Journal of Biological Chemistry.

[25]  E. Feinstein,et al.  Altered nutrient response of mTORC1 as a result of changes in REDD1 expression: effect of obesity vs. REDD1 deficiency. , 2014, Journal of applied physiology.

[26]  S. Kimball,et al.  REDD1 enhances protein phosphatase 2A–mediated dephosphorylation of Akt to repress mTORC1 signaling , 2014, Science Signaling.

[27]  E. Ropelle,et al.  Effects of Physical Exercise on the P38MAPK/REDD1/14-3-3 Pathways in the Myocardium of Diet-Induced Obesity Rats , 2014, Hormone and Metabolic Research.

[28]  S. Kimball,et al.  Regulated in DNA damage and development 1 (REDD1) promotes cell survival during serum deprivation by sustaining repression of signaling through the mechanistic target of rapamycin in complex 1 (mTORC1). , 2013, Cellular signalling.

[29]  H. Miyahara,et al.  Diet high in fat and sucrose induces rapid onset of obesity-related metabolic syndrome partly through rapid response of genes involved in lipogenesis, insulin signalling and inflammation in mice , 2012, Diabetology & Metabolic Syndrome.

[30]  P. Walter,et al.  The Unfolded Protein Response: From Stress Pathway to Homeostatic Regulation , 2011, Science.

[31]  P. Schrauwen,et al.  Lipotoxicity in type 2 diabetic cardiomyopathy. , 2011, Cardiovascular research.

[32]  J. Egido,et al.  Potential Role of Nuclear Factor κB in Diabetic Cardiomyopathy , 2011, Mediators of inflammation.

[33]  P. Kolattukudy,et al.  Hyperglycaemia-induced cardiomyocyte death is mediated via MCP-1 production and induction of a novel zinc-finger protein MCPIP. , 2010, Cardiovascular research.

[34]  S. Biswal,et al.  Rtp801, a suppressor of mTOR signaling, is an essential mediator of cigarette smoke – induced pulmonary injury and emphysema , 2010, Nature Medicine.

[35]  W. Min,et al.  The signal transduction pathway of PKC/NF-κB/c-fos may be involved in the influence of high glucose on the cardiomyocytes of neonatal rats , 2009, Cardiovascular diabetology.

[36]  S. Kimball,et al.  ATF4 is necessary and sufficient for ER stress-induced upregulation of REDD1 expression. , 2009, Biochemical and biophysical research communications.

[37]  J. Mazière,et al.  Activation of transcription factors and gene expression by oxidized low-density lipoprotein. , 2009, Free radical biology & medicine.

[38]  Merlin C. Thomas,et al.  Cardiac inflammation associated with a Western diet is mediated via activation of RAGE by AGEs. , 2008, American journal of physiology. Endocrinology and metabolism.

[39]  R. Wek,et al.  Translational control and the unfolded protein response. , 2007, Antioxidants & redox signaling.

[40]  Guanghui Liu,et al.  Involvement of Endoplasmic Reticulum Stress in Myocardial Apoptosis of Streptozocin-Induced Diabetic Rats , 2007, Journal of clinical biochemistry and nutrition.

[41]  P. Einat,et al.  Inhibition of oxygen-induced retinopathy in RTP801-deficient mice. , 2004, Investigative ophthalmology & visual science.

[42]  Jon R Lorsch,et al.  GTP-dependent recognition of the methionine moiety on initiator tRNA by translation factor eIF2. , 2004, Journal of molecular biology.

[43]  S. Chakrabarti,et al.  Differential activation of NF-kappa B and AP-1 in increased fibronectin synthesis in target organs of diabetic complications. , 2003, American journal of physiology. Endocrinology and metabolism.

[44]  R. Paules,et al.  An integrated stress response regulates amino acid metabolism and resistance to oxidative stress. , 2003, Molecular cell.

[45]  A. Grishman,et al.  New type of cardiomyopathy associated with diabetic glomerulosclerosis. , 1972, The American journal of cardiology.

[46]  L. Velloso,et al.  Endoplasmic reticulum stress, obesity and diabetes. , 2012, Trends in molecular medicine.

[47]  M. McGuinness,et al.  NF-kappaB as an integrator of diverse signaling pathways: the heart of myocardial signaling? , 2003, Cardiovascular toxicology.

[48]  D. Bell,et al.  Diabetic cardiomyopathy. , 2003, Diabetes care.