ABSTRACT
RATIONALE: Maintaining iron homeostasis is essential for proper cardiac function. Both iron deficiency and iron overload are associated with cardiomyopathy and heart failure via complex mechanisms. Although ferritin plays a central role in iron metabolism by storing excess cellular iron, the molecular function of ferritin in cardiomyocytes remains unknown. OBJECTIVE: To characterize the functional role of Fth (ferritin H) in mediating cardiac iron homeostasis and heart disease. METHODS AND RESULTS: Mice expressing a conditional Fth knockout allele were crossed with 2 distinct Cre recombinase-expressing mouse lines, resulting in offspring that lack Fth expression specifically in myocytes (MCK-Cre) or cardiomyocytes (Myh6-Cre). Mice lacking Fth in cardiomyocytes had decreased cardiac iron levels and increased oxidative stress, resulting in mild cardiac injury upon aging. However, feeding these mice a high-iron diet caused severe cardiac injury and hypertrophic cardiomyopathy, with molecular features typical of ferroptosis, including reduced glutathione (GSH) levels and increased lipid peroxidation. Ferrostatin-1, a specific inhibitor of ferroptosis, rescued this phenotype, supporting the notion that ferroptosis plays a pathophysiological role in the heart. Finally, we found that Fth-deficient cardiomyocytes have reduced expression of the ferroptosis regulator Slc7a11, and overexpressing Slc7a11 selectively in cardiomyocytes increased GSH levels and prevented cardiac ferroptosis. CONCLUSIONS: Our findings provide compelling evidence that ferritin plays a major role in protecting against cardiac ferroptosis and subsequent heart failure, thereby providing a possible new therapeutic target for patients at risk of developing cardiomyopathy.
Subject(s)
Amino Acid Transport System y+/metabolism , Apoferritins/deficiency , Cardiomyopathies/etiology , Ferroptosis/physiology , Iron/metabolism , Myocardium/metabolism , Aging , Alleles , Animals , Apoferritins/adverse effects , Apoferritins/genetics , Cardiomyopathies/metabolism , Cardiomyopathies/prevention & control , Cardiomyopathy, Hypertrophic/etiology , Cardiomyopathy, Hypertrophic/prevention & control , Crosses, Genetic , Cyclohexylamines/administration & dosage , Glutathione/metabolism , Heart Failure/etiology , Homeostasis , Hypertrophy, Left Ventricular/etiology , Iron Deficiencies , Iron Overload , Iron, Dietary/adverse effects , Lipid Peroxidation , Male , Mice , Mice, Transgenic , Myocytes, Cardiac/metabolism , Oxidative Stress , Phenylenediamines/administration & dosage , Reactive Oxygen Species/metabolismABSTRACT
Herein, we describe the in vivo effects of doxorubicin (DOX) encapsulated in ubiquitous protein apoferritin (APO) and its efficiency and safety in anti-tumor treatment. APODOX is both passively (through Enhanced Permeability and Retention effect) and actively targeted to tumors through prostate-specific membrane antigen (PSMA) via mouse antibodies conjugated to the surface of horse spleen APO. To achieve site-directed conjugation of the antibodies, a HWRGWVC heptapeptide linker was used. The prostate cancer-targeted and non-targeted nanocarriers were tested using subcutaneously implanted LNCaP cells in athymic mice models, and compared to free DOX. Prostate cancer-targeted APODOX retained the high potency of DOX in attenuation of tumors (with 55% decrease in tumor volume after 3 weeks of treatment). DOX and non-targeted APODOX treatment caused damage to liver, kidney and heart tissues. In contrast, no elevation in liver or kidney enzymes and negligible changes were revealed by histological assessment in prostate cancer-targeted APODOX-treated mice. Overall, we show that the APO nanocarrier provides an easy encapsulation protocol, reliable targeting, high therapeutic efficiency and very low off-target toxicity, and is thus a promising delivery system for translation into clinical use.
Subject(s)
Apoferritins/therapeutic use , Doxorubicin/analogs & derivatives , Immunoconjugates/therapeutic use , Nanoconjugates/therapeutic use , Prostatic Neoplasms/therapy , Animals , Antigens, Surface/immunology , Apoferritins/adverse effects , Cell Line, Tumor , Doxorubicin/adverse effects , Doxorubicin/therapeutic use , Glutamate Carboxypeptidase II/immunology , Heart/drug effects , Heterografts , Humans , Kidney/drug effects , Liver/drug effects , Male , Mice , Mice, Inbred BALB C , Mice, Nude , Prostatic Neoplasms/drug therapy , Treatment Outcome , Xenograft Model Antitumor AssaysABSTRACT
The chemokine CXCL12 and its receptor, CXCR4, regulate neuronal migration, differentiation, and survival. Alterations of CXCL12/CXCR4 signaling are implicated in different neuropathologies, including the neurological complications of HIV infection. Opiates are important co-factors for progression to neuroAIDS and can disrupt the CXCL12/CXCR4 axis in vitro and in vivo. This paper will review recently identified mechanisms of opiate-induced CXCR4 impairment in neurons and introduce results from pilot studies in human brain tissue, which highlight the role of the protein ferritin heavy chain in HIV neuropathology in patients with history of drug abuse.
