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Apoptosis-related Diseases

Apoptosis-related Diseases. Insufficient apoptosis Excessive apoptosis Coexistence of insufficient and excessive apoptosis. Apoptosis. Growth. Balance of Growth and Apoptosis. Apoptosis and Diseases. Diseases Mechanism Apoptosis. Heart failure.

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Apoptosis-related Diseases

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  1. Apoptosis-related Diseases • Insufficient apoptosis • Excessive apoptosis • Coexistence of insufficient and excessive apoptosis

  2. Apoptosis Growth Balance of Growth and Apoptosis

  3. Apoptosis and Diseases Diseases Mechanism Apoptosis Heart failure Ischemia, inflammation, etc. AIDS HIV infection of T4 cell AD, PD Ischemia, inflammation, etc Cancer P53, Bcl-2 Autoimmune diseases Autoreactive T cells or B cells Atherosclerosis Endothelial cell, muscle cell

  4. Apoptosis Genes mutated in Diseases Gene Affected disease Tumor necrosis factor Familial periodic fever syndrome receptor 1 (TNF-R1) Fas (CD95; Apo-1) Autoimmune lymphoproliferative syndrome type I(ALPS I), malignant lymphoma, bladder cancer Fas ligand Systemic lupus erythematodes Perforin Familial hemophagocytic lymphohistiocytosis (FHL) Caspase 10 Autoimmune lymphoproliferative syndrome type II (ALPS II) bcl-10 Non-Hodgkin’s lymphoma p53 Various malignant neoplasms Bax Colon cancer; hematopoetic malignancies bcl-2 Non-Hodgkin’s lymphoma c-IAP2 Low-grade MALT lymphoma NAIP1 Spinal muscular atrophy

  5. Insufficient Apoptosis in Diseases Autoimmune disease, Tumor, virus infection, etc Proliferation Apoptosis

  6. (1) Tumor Pathogenesis for tumor: stimulated cell proliferation inhibited cell apoptosis Cell survival > cell death in diseased tissue Cell apoptosis is actually one of the natural anti-carcinogenic mechanisms

  7. Signaling Pathways Involved in Apoptosis(Molecules highlighted in red have been found mutated in tumor cells)

  8. Tumor----P53 mutation Chemicals Virus Radiation

  9. (2) Autoimmune diseases The lesion is caused by attack of auto-antibody or sensitized T cell to self-antigen. Normally, T cells against auto-antigen are eliminated by apoptosis during the development. When the negative selection is deregulated (thymus diseases), T cells survive and abnormally proliferate, then attack self tissue, lead to autoimmune diseases.

  10. Mechanism of autoimmune diseases — Disrupted apoptosis of self-reactive cell Insertion mutation of Fas Point mutation of FasL Structural abnormity of FasL Decreased expression of Fas protein Escape the negative selection of self-reactive T cells Autoimmune diseases

  11. Rheumatoid arthritis • It is caused by decreased apoptosis and increased proliferation of arthral cell ; • Increased IL-1 and TGF-β1 and decreased Fas expression, which inhibit apoptosis; • Increased Bcl-2、Bcl-XL, which increased the threshold of apoptosis; • Resistance of T-cells to apoptosis.

  12. Excessive Apoptosis in Diseases AIDS, neurodegenerative diseases, aberrant myocardial ischemic-reperfusion

  13. （1）Acquired Immune Deficiency Syndrome —AIDS HIV infection increased Fas gene expression gp120glycoprotein expression + receptor in CD4 lymphocyte infusion of infected CD4 cell leads to syncytin formation produce tat protein (enhance Fas expression) secret TNF CD+4T- lymphocyte apoptosis AIDS

  14. (2) Cardiovascular diseases Cell death induced by ischemia-reperfusion Apoptosis Necrosis Early stage Later stage Peripheral region of infarct Center of infarct Mild ischemia Severe ischemia Chronic Acute

  15. Possible mechanism (myocardial cell apoptosis induced by ischemia-reperfusion): (1) oxidative stress; (2) calcium overload; (3) p53 gene activation; (4) death receptor Fas, TNF over expressed.

  16. Heart failure: Myocardial cell diminishes in pressure- overload-induced heart failure Possible mechanisms: Oxidative stress; cytokines; ischemia; hypoxia; pressure or volume overload, neural-endocrine system deregulation; Lead to myocardial cell apoptosis

  17. （3）Neurodegenerative diseases Alzheimer disease，Parkinson disease，Huntington disease，multiple sclerosis Factors involved in neuronal apoptosis: b-amyloid peptide, calcium overload, oxidative stress, neuronal growth factor insufficiency, etc. Lead to neuronal cell apoptosis

  18. oxidative LDL platelet activation AngⅡ hypertension excess apoptosis insufficiency in in endothelium smooth muscle atherosclerosis Coexistence of Excessive and Insufficient Apoptosis in Diseases

  19. Prevention and Therapeutic Potential of Apoptosis • Interfere signal transduction, signal molecules, • receptors, 2nd messengers, etc • Regulate apoptosis-related enzymes and genes • Prevent decrease in mitochondria trans-membrane • potential • Others

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