114 Plenary lectures 

STRUCTURAL AND PHYSIOLOGICAL ASPECI'S OF & l ? K X M l ~  HEPARIN.. Alan A. 

H o r n e r  (Department of Physiology, University of Toronto, Toronto, Ontario 
Canada). 

Evidence w i l l  be presented that the s t r u c t u r a l  i n t e g r i t y  of macro- 
molecular heparin, the multi-chain fonn of heparin isolated fram pronase- 
digested r a t  skin (Horner, J. Biol. Chem. 246, 231, 1971) depends on a 
unique polypeptide core containing only s e r i n e  and glycine i n  equim0lar 
p r q r t i o n s .  

degradation studies using alkali i n  t h e  presence of H-borohydride, n i t r o u s  
acid and an endqlycosidase present i n  muse mastocytml t i s s u e  (Robinson, 
Horner, H z k ,  &ren and Lindahl, manuscript in preparation) . 

The data supporting the proposed structure is derived f r a n  
3 

It follows f r a n  this nodel that t h e  individual heparin chains linked 
t o  the polypeptide core are considerably longer than those of ccormercial 

heparin. 
(Young and Homer, manuscripts i n  preparation), of the sequential break- 
dawn of m a c r m l e c u l a r  heparin by several depolymrases present i n  normal 

rat tissues, yielding chains i n  t h e  same molecular s i z e  range as c o m r c i a l  
heparins. 
endoqlycosidase in t h a t  products of d i f f e r e n t  s i z e s  are produced. 

small i n t e s t i n e  contains two depolymrase a c t i v i t i e s  with pH o p t h a  of 6.0 

arYj 7.4, w h i l s t  plasma contains a c t i v i t y  w i t h  a pH o p t i m u m  of 6.0 only. 
The plasma e n z p  p r d u c t  fonned a t  pH 6.0 is l a r g e r  than t h e  i n t e s t i n a l  
enzyme product formed a t  pH 6.0. These depolymerizing enzymes are not 
necessarily a l l  endqlycosidases, one may cleave t h e  proposed polypeptide 

core structure. 

Examples w i l l  be given, fram work i n  progress i n  t h i s  laboratory 

These enzyms appear t o  act d i f f e r e n t l y  f r m  the mastocytomal 

The 

The possible physiological significance of t h e  breakdmm of macro- 
molecular heparin i n  vivo w i l l  be discussed, with p a r t i c u l a r  reference t o  
the r e l a t i o n s h i p  betwen endogenous heparin arid lipoprotein lipase. The 
pathological jmplications of impaired depolymerization of macranolecular 

heparin have been studied i n  an i n d i r e c t  manner by feeding an atherogenic 
d i e t  t o  squirrel mnkeys. 
m e a n s  was a c c q a n i e d  by t h e  accumulation of macromolecular heparin i n  the 
small i n t e s t i n e ,  a t i s s u e  in which only low m l e c u l a r  weight heparin was 

found i n  healthy m n t r o l s .  Macromolecular heparin inhibits lipoprotein 
l i p a s e  a c t i v i t y  i n  v i t r o  (Homer, Prcc. N a t .  Acad. Sci. U.S.A. 6 9 ,  3469, 
1972). 

support the hypothesis of Z i l v e r s n i t  (Circulation Res. 2, 633, 1973) 
which contends t h a t  lipoprotein l i p a s e  and endogenous heparin are s i g n i f -  

icant factors in the a e t i o l q y  of atherosclerosis. 
demonstrates that the enzymic depolymerization of m a c r m l e c u l a r  heparin 
is an additional f a c t o r  which must be considered. 

The induction of atherosclerosis by d i e t a r y  

- 
Therefore the r e s u l t s  of the s q u i r r e l  monkey feeding experiment 

The present work 

Upsala J Med Sci 82