A NEW STRATEGY
---TO TREAT/PREVENTE HYPERHOMOCYSTEINEMIA
Chaoshu Tang
Homocysteine (HCY) is a sulfur-containing amino acid produced during catabolism of the essential amino acid methionine.
Homocysteine metabolism
HYPERHOMOCYSTEINEMIA
Normal human plasma HCY concentration
5-15μmol/L
Hyperhomocysteinemia
16-30μmol/L
30-100μmol/L
>100μmol/L
Hyperhomocysteinemia an independent cardiovascular risk factor
Mechanism of Cell injury by HCY
Oxidative stress
Inflammation pathway
Endoplasmic reticulum stress
VSMCs over—proliferation
Interfere lipid metabolism
Interfere endothelia coagulation activities
Interfere L-arg-NOS/NO pathway
Clinical therapy and current questions
Vitamin B6,B12 and folic acid—the main treatment strategy
Indication
neural degeneration
Endothelia protection per se
Betaine
N-athelcysteine, NAC ; Vit E
Peptides---- CNP, ADM, CGRP etc.
Hormone
Drugs
Therapeutic New strategy to hyperhomocysteinemia
Sulfur-containing amino acid metabolism system ---- super regulation family
Generation from the methionine
Independent biological effects
Interactive regulation and antagonism
Endogenous antagonist as a new therapy /prevention for hyperhomocysteinemia ???
Taurine
Regulate osmotic pressure
Stabilize cell membrane
Regulation free Ca2+
Inhibit lipid peroxidation
Regulate endothelia contraction/relaxation factor synthesize/release
AS an endogenous protectant in various diseases including cardiovascular diseases
Antagonism to cardiovascular injury by HCY
Endothelia Injury
structure disorder
ET release
LDH release
Proliferation
VSMCs proliferation
Myocardium
HCY lowered tautrine concentration
Inhibit taurine uptake
Increase taurine release
Mitochondria Injury
Methinine food induced hyperhomocysteinemia
Myocardial Mitochondria (×40 000)
Control Tau alone
Met alone Met+ Tau
Taurine antagonism to HCY cardiovascular injury by oxidative stress
Mitochondria membrane Lipid peroxidation
MDA
Conjugated diene
Myocardial Mitochondria O2- production and Mn-SOD activity
Mn-SOD
Myocardial Mitochondria H2O2 production and CAT activity
CAT
**p<0.01 vs control; #p<0.05, ##p<0.01 vs Met
Myocyte H2O2 production
a
b
Myocyte
Mitochondria H2O2 production in vitro
Mitochondria O2- production in vitro
Sub-mitochondria H2O2 and O2-
Mitochondria enzyme-complex-II and III recombination H2O2 O2- production
Disoxidation cytochrome-C leakage
A
B
Endoplasmic Reticulum Stress pathway
VMSC GRP78 mRNA expression and PERK phosphorylation
VMSC EC-SOD mRNA and protein expression
Hydrogen Sulfide (H2S)
Relax the VSMCs by opening the KATP channel, in a independent endothelia manner and in synergy with NO
A transient hypotension effect by bolus injection H2S
Inhibit the VSMCs proliferation by MAPK pathway
A transient negative inotropic effect on myocardium mediated by the KATP channel
Decrease the central venous pressure by bolus injection
Respiration control rate of mitochondria
H2S inhibit H2O2 release induced by HCY, and the direct scavenge H2O2 and O2-
H2S inhibit ER stress induced by Hcy
Metallothionein (MT)
Regulate metal ion metabolism
Deintoxication of heavy non-ferrous metals
Scavenge oxygen free radicals
Stabilize biomembranes.
Endothelia injury
VSMCs proliferation and injury
Vascular fibroblast activation
PROSPECT
Endogenous antagonist from the same family might be a new strategy of treatment/prevention hyperhomocysteinemia
谢 谢 ！