Apoptosis-related Diseases

Apoptosis-related DiseasesApoptosis-related DiseasesApoptosis-related DiseasesApoptosis-related Diseases

Insufficient apoptosis Excessive apoptosis Coexistence of insufficient and

excessive apoptosis

Growth Apoptosis

Balance of Growth and ApoptosisBalance of Growth and ApoptosisBalance of Growth and ApoptosisBalance of Growth and Apoptosis

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

Apoptosis and DiseasesApoptosis and DiseasesApoptosis and DiseasesApoptosis and Diseases

Gene Affected diseaseTumor necrosis factor Familial periodic fever syndrome receptor 1 (TNF-R1)Fas (CD95; Apo-1) Autoimmune lymphoproliferative syndrome type I(ALPS I), malignant lymphoma, bladder cancerFas ligand Systemic lupus erythematodesPerforin Familial hemophagocytic lymphohistiocytosis (FHL)Caspase 10 Autoimmune lymphoproliferative syndrome type II (ALPS II)

bcl-10 Non-Hodgkin’s lymphomap53 Various malignant neoplasmsBax Colon cancer; hematopoetic malignanciesbcl-2 Non-Hodgkin’s lymphomac-IAP2 Low-grade MALT lymphomaNAIP1 Spinal muscular atrophy

Apoptosis Genes mutated in DiseasesApoptosis Genes mutated in DiseasesApoptosis Genes mutated in DiseasesApoptosis Genes mutated in Diseases

Autoimmune disease,Tumor, virus infection, etc

Proliferation

Apoptosis

Insufficient Apoptosis in DiseasesInsufficient Apoptosis in DiseasesInsufficient Apoptosis in DiseasesInsufficient Apoptosis in Diseases

(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

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

Tumor----P53 mutation

ChemicalsVirusRadiation

(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.

Mechanism of autoimmune diseases — Disrupted apoptosis of self-reactive cell

Point mutation of FasL

Insertion mutation of Fas

Structural abnormity of FasL

Decreased expression of Fas protein

Escape the negative selection of self-reactive

T cells

Autoimmune diseases

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.

AIDS, neurodegenerative diseases, aberrant myocardial ischemic-reperfusion

Excessive Apoptosis in DiseasesExcessive Apoptosis in DiseasesExcessive Apoptosis in DiseasesExcessive Apoptosis in Diseases

（ 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

(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

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.

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

Alzheimer disease ， Parkinson disease ， Huntington disease ， multiple sclerosis

Factors involved in neuronal apoptosis:

amyloid peptide, calcium overload,

oxidative stress, neuronal growth factor insufficiency,

etc.

Lead to neuronal cell apoptosis

（ 3 ） Neurodegenerative diseases

oxidative LDL

platelet activation Ang Ⅱ

hypertension

excess apoptosis insufficiency in in endothelium smooth muscle

atherosclerosis

Coexistence of Excessive and Coexistence of Excessive and Insufficient Apoptosis in DiseasesInsufficient Apoptosis in Diseases

Coexistence of Excessive and Coexistence of Excessive and Insufficient Apoptosis in DiseasesInsufficient Apoptosis in Diseases

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