Cardioprotective effects of cerium oxide nanoparticles in a transgenic murine model of cardiomyopathy.
OBJECTIVE
Cerium oxide (CeO2) nanoparticles have been shown to protect cells in culture from lethal stress, but no protection in vivo has been reported. Cardiac-specific expression of monocyte chemoattractant protein (MCP)-1 in mice causes ischemic cardiomyopathy associated with activation of endoplasmic reticulum (ER) stress. The aim of this study was to assess the effects of CeO2 nanoparticles on cardiac function and remodeling as well as ER stress response in this murine model of cardiomyopathy.


METHODS
MCP-1 transgenic mice (MCP mice) and wild-type controls were administered intravenously 15 nmol of CeO2 nanoparticles or vehicle only twice a week for 2 weeks. Cardiac function, myocardial histology, nitrotyrosine formation, expression of cytokines, and ER stress-associated genes were evaluated.


RESULTS
Treatment with CeO2 nanoparticles markedly inhibited progressive left ventricular dysfunction and dilatation in MCP mice and caused a significant decrease in serum levels of MCP-1, C-reactive protein, and total nitrated proteins. The infiltration of monocytes/macrophages, accumulation of 3-nitrotyrosine, apoptotic cell death, and expression of proinflammatory cytokines, tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and IL-6 in the myocardium were markedly inhibited by CeO2 nanoparticles. Expression of the key ER stress-associated genes, including glucose-regulated protein 78 (Grp78), protein disulfide isomerase (PDI), and heat shock proteins (HSP25, HSP40, HSP70), were also suppressed by CeO2 nanoparticles.


CONCLUSIONS
CeO2 nanoparticles protect against the progression of cardiac dysfunction and remodeling by attenuation of myocardial oxidative stress, ER stress, and inflammatory processes probably through their autoregenerative antioxidant properties.
Niu
Jianli
J
Biomolecular Science Center, Burnett College of Biomedical Science, University of Central Florida, Orlando, FL 32816, USA.
Azfer
Asim
A
Rogers
Linda M
LM
Wang
Xihai
X
Kolattukudy
Pappachan E
PE
D000818:Animals; D002097:C-Reactive Protein / Q000032:analysis; D009202:Cardiomyopathies / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D002563:Cerium / Q000008:administration & dosage* / Q000627:therapeutic use; D018932:Chemokine CCL2 / Q000097:blood / Q000235:genetics; D004452:Echocardiography; D004721:Endoplasmic Reticulum / Q000276:immunology / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D016166:Free Radical Scavengers / Q000008:administration & dosage* / Q000627:therapeutic use; D015870:Gene Expression; D005819:Genetic Markers; D006360:Heat-Shock Proteins / Q000235:genetics; D006801:Humans; D053583:Interleukin-1beta / Q000032:analysis / Q000235:genetics; D015850:Interleukin-6 / Q000032:analysis / Q000235:genetics; D008264:Macrophages / Q000276:immunology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000276:immunology / Q000378:metabolism*; D053758:Nanoparticles / Q000032:analysis / Q000627:therapeutic use; D009569:Nitric Oxide / Q000097:blood; D018384:Oxidative Stress / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000235:genetics; D018487:Ventricular Dysfunction, Left; D020257:Ventricular Remodeling
D018932:Chemokine CCL2; D000091342:Endoplasmic Reticulum Chaperone BiP; D016166:Free Radical Scavengers; D005819:Genetic Markers; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D053583:Interleukin-1beta; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D002563:Cerium; D009569:Nitric Oxide; C030583:ceric oxide; D002097:C-Reactive Protein