Download Cardiovascular diseases

Apoptosis and Diseases
Contents
1.
2.
3.
4.
Concept
Major pathways
Key molecules
Apoptosis-related diseases
• Insufficient apoptosis in diseases
• Excessive apoptosis in diseases
• Coexistence of insufficient and excessive
apoptosis in diseases
5. Principles of treatment
History of Cell Death Research
Using C. elegan as a model
Apoptosis or Programmed Cell Death
pre-programed, cascade events ATP, gene expression
A highly regulated active cell death
characterized by cell shrinkage and
nuclear condensation.
Morphology opposite to necrosis
What is the difference of programmed cell death and apoptosis?
Apoptosis and Necrosis
Apoptosis
Necrosis
Nature
Physiological or
pathological; specific
Pathological, accidental
Stimulus
Mild
Strong
Biochemistry
Active, energy-dependent,
new protein synthesis
Passive, energy-independent, no
protein synthesis
DNA
Specific degradation,
ladder (180-200 bp)
Intact, shrinkage,
condensation
Random degradation
Inflammation
No
Yes
Apoptotic body
Yes
No
Gene regulation
Yes
No
Morphology
Lysis, swelling
Apoptotic Process
Stimulatory Factors
Inhibitory Factors
Physiological, e.g., growth
factors, estrogen; virus;
chemicals.
Initiation
Regulation
Conserved
Execution
Phagocytosis
Physiological, FasL;
Pathological, glutamate, free radicals;
therapeutical, herb.
Conserved apoptotic paradigms in C.
elegans, Drosophia, and mammals
Apoptotic Pathways
• Death receptor-mediated apoptotic
pathway
• Mitochondria-mediated apoptotic
pathway
• Nuclear-mediated apoptotic pathway
Apoptotic Pathways
death-inducing
signaling complex
Fas-associating
protein with
death domain
Mitochondrial Membrane Permeabilization
(MMP) in Apoptotic Process
ER and Apoptosis
Cross-talking among Organelles and Molecules in Apoptosis
Executors
1. Activation of endonuclease
2. Activation of caspases
DNA ladder
Collapse of cell and nucleus
Role of Endonuclease
180-200 bp
Endonuclease
Zn2+
H1
Ca2+ Mg2+
Role of Caspases
(p21-activated kinase 2)
(Ste20-related kinase)
(Focal adhesion kinase)
Phosphatidylserine (PS) receptor (PSR) acts as a ‘tickle’ receptor
for uptake of apoptotic cells
Key Molecules
1. Caspases: Caspase-3,Caspase-8,Caspase-9, etc.
2. Bcl-2 family：
anti-apoptotic: Bcl-2 (B cell lymphoma/leukemia), Bcl-XL
pro-apoptotic: Bax, Bad
3. Others: Apaf-1(apoptosis activating factor-1),
cytochrome C, IAPs, p53, etc.
Table 1. Caspase-deficient miceKnockout Phenotype
Caspase-1 Viable; impaired processing of IL-1; resistant to endotoxic shock.
Caspase-2 Viable; excess numbers of female germ cells; oocytes resistant to
chemotherapeutic drugs; B lymphoblasts resistant to granzyme B;
accelerated death of facial neurons during development and of
sympathetic neurons deprived of NGF.
Caspase-3 Lethality at 3–5 weeks of age; defective neuronal apoptosis; T cells
resistant to antigen-induced death; abnormal apoptotic morphology in
dying cells.
Caspase-8 Lethality around E12.5; hyperemia and abnormal heart muscle
development; MEFs resistant to TNF, Fas and DR3 but sensitive to
UV irradiation, etoposide, staurosporine, serum deprivation.
Caspase-9 Perinatal lethal; impaired neuronal apoptosis; ES cells, MEFs and
thymocytes generally resistant to intrinsic death stimuli such as
DNA damage, though resistance depends on cell type.
Caspase-11 Viable; impaired processing of caspase-1, IL-1; resistant to endotoxic
shock.
Caspase-12 Viable; embryonic fibroblasts are resistant to ER stress.
Apoptosis-related Diseases
Balance of Growth and Apoptosis
Growth
Apoptosis
Insufficient Apoptosis in Diseases
Autoimmune disease,
Tumor, virus infection, etc
Proliferation
Apoptosis
(1) Tumor
Pathogenesis for tumor:
stimulated cell proliferation
inhibited cell apoptosis
Cell survival > cell death in diseased tissue
Etiologically, cell apoptosis is actually one of the
natural anti-carcinogenic mechanisms
(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
Insertion
mutation of Fas
Decreased expression of
Fas protein
Point mutation
of FasL
Structural
abnormity of FasL
Escape the negative
selection of self-reactive
T cells
Autoimmune diseases
Rheumatoid arthritis
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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.
Excessive Apoptosis in Diseases
AIDS, neurodegenerative
diseases, aberrant
myocardial ischemicreperfusion
（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
Early stage
Peripheral region of infarct
Mild ischemia
Chronic
Necrosis
Later stage
Center of infarct
Severe ischemia
Acute
Cardiovascular diseases (cont.)
Possible mechanism (myocardial cell apoptosis
induced by ischemia-reperfusion):
(1)
(2)
(3)
(4)
oxidative stress;
calcium overload;
p53 gene activation;
death receptor Fas, TNF over expressed.
Cardiovascular diseases (cont.)
Heart failure:
Myocardial cell diminishes in pressureoverload-induced heart failure
Possible mechanisms:
Oxidative stress; cytokines; ischemia;
hypoxia; pressure or volume overload,
neural-endocrine system deregulation;
Lead to myocardial cell apoptosis
（3） Neurodegenerative diseases
Alzheimer disease，Parkinson disease，
Huntington disease， multiple sclerosis
Factors involved in neuronal apoptosis:
b-amyloid peptide, calcium overload,
oxidative stress and neuronal growth factor
insufficiency, etc.
Lead to neuronal cell apoptosis
Coexistence of Excessive and
Insufficient Apoptosis in Diseases
Coexistence of Excessive and
Insufficient Apoptosis
oxidative LDL
platelet activation
AgⅡ
hypertension
excess apoptosis
in endothelium
insufficiency in
smooth muscle
atherosclerosis
Apoptosis and Diseases
Diseases
Heart failure
AIDS
AD, PD
Cancer
Autoimune diseases
Atherosclerosis
Mechanism
Apoptosis
Ischemia, inflammation, etc.
HIV infection of T4 cell
Ischemia, inflammation, etc
P53, Bcl-2
Autoreactive T cells or B cells
Endothelial cell, muscle cell
Apoptosis Genes mutated in Diseases
Gene
Tumor necrosis factor
receptor 1 (TNF-R1)
Fas (CD95; Apo-1)
Fas ligand
Perforin
Caspase 10
bcl-10
p53
Bax
bcl-2
c-IAP2
NAIP1
Affected disease
Familial periodic fever syndrome
Autoimmune lymphoproliferative syndrome
type I(ALPS I), malignant lymphoma,
bladder cancer
Systemic lupus erythematodes
(only one case identified)
Familial hemophagocytic lymphohistiocytosis (FHL)
Autoimmune lymphoproliferative syndrome
type II (ALPS II)
Non-Hodgkin’s lymphoma
Various malignant neoplasms
Colon cancer; hematopoetic malignancies
Non-Hodgkin’s lymphoma
Low-grade MALT lymphoma
Spinal muscular atrophy
Principle of Treatment
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