Pyridoxine, Atherosclerosis and Diabetes
Yong Ji
Atherosclerosis Research Center
NanJing Medical University
BACKGRAUND:
Atherosclerosis (AS) –the principal cause of heart attack, stroke and gangrene of the extremities, is responsible for 50% of all mortality in the USA, Europe and Japan and is predicted by WHO to be most common cause of death in the world in 2020.
An impairment of the endothelium-dependent vasodilatory response (EDR) is present in atherosclerotic vessels. However, NO plays an important role in the protection against the onset and progression of cardiovascular disease.
The impaired EDR represents the reduced eNOS-derived NO activity. And this may due either to suppression of eNOS activity or expression.
--- Kawashima S.J Pharmacol Sci. 2004 Dec;96(4):411-9.
Promote vasorelaxation
Prevent leukocytes adhesion and platelet aggregation
Inhibit vascular permeability
Inhibit atherogenesis
Supplementation with either L-ariginine or L-ascorbate can ameliorate NO production through beneficial effects on NOS activity.
---Y. Ji , Qi Chen et al. / Atherosclerosis 176 (2004) 345–353
L-arginine
L-citrulline
eNOS
O2
NADPH
NO
NADP
The treatments of AS:
Normal treatments: Aspirin
(Peter D.O’Kane, YongJi et.al. Cardiovascular Research 59(2003)152-159)
Beta-blocker
(L.R.Queen, Yong Ji et.al.Diabetologia(2003)46:1474-1482)
(Ferro A, Yong Ji et al. Br J Pharmacol. 2004 Oct;143(3):397-403.）
ACEI
(Kubo SH et al.Circulation 1991; 83: 391–401. 94.)
Statins
(Peter Libby et al. Curr Atheroscler Rep. 2002 May;4(3):211-2 )
A “novel” medicine : Pyridoxine
pyridoxine: a potential medicine
1.Homocysteine and AS
Hyperhomocysteinemia induces vascular endothelial dysfunction, contributing to a predisposition to the onset and/or progression of atherosclerosis.
2. Pyridoxine and homocysteine
VB6
VB6
3. Pyridoxine can prevent LDL-induced dysfunction of
endothelial cell NO generations.
---Y. Ji, Ferro A et al. British Journal of Pharmacology (2003) 140, 1272–1282
1. LDL species decrease cystathionine and increase homocysteine
concentrations in HUVEC, effects which are largely prevented by
pyridoxine.
Yong JI et al .Atherosclerosis (in press)
TABLE 2. Amino acid concentrations in HUVEC: effect of LDL species (100 mg protein/L) and of pyridoxine
*, **, *** P < 0.05, < 0.01 and < 0.001 respectively as compared with control
#, ## P < 0.05 and < 0.01 respectively as compared with absence of pyridoxine
Figure 1. LDL species concentration-dependently decrease total NOS activity whilst increasing calcium-independent NOS activity. *, ** P < 0.05 and < 0.01 as compared to control.
Yong JI et al .Atherosclerosis (in press)
2. Pyridoxine prevents the LDL-induced suppression of NO biosynthesis by HUVEC. (figure 1-4)
nLDL
dLDL
oxLDL
nLDL
dLDL
oxLDL
Figure 2: LDL species concentration-dependently decrease intracellular c