ALTERATIONS IN DNA SYNTHESIS AND OTHER 
METABOLIC PROCESSES IN AORTAS OF 
CHOLESTEROL-FED SWINE 
W. A. Thomas, R. A. Florentin, S. C. Nam 
J. M. Reiner and K. T. Lee* 
Swine fed a high fat-cholesterol diet begin to develop 
gross atherosclerotic lesions in 1-2 months. The most 
prominent histologic features of the early gross lesions 
are excessive accumulation of lipid-laden smooth mus- 
cle cells (SMC), collagen, elastin and mucopolysac- 
charides in arterial intimas. Metabolic and cell kinetic 
studies of the gross lesions indicate increased rates of 
DNA and protein synthesis, oxygen consumption and 
cell division. Electron microscopy studies show changes 
in a majority of SMC that are consistent with increased 
activity; however a significant minority are degenerat- 
ing or dead. Investigation of metabolic and cell kinetic 
changes that occur in arteries of high fat-cholesterol-fed 
swine prior to development of atherosclerotic lesions 
recognizable by either gross or light microscopy have 
been made. As early as 3 days on high fat-cholesterol 
. diet increased rates of DNA synthesis, oxygen uptake 
and cell division can be demonstrated. By electron mi- 
croscopy a small but significantly increased number of 
dead or degenerating cells can be seen. Studies of the 
cell cycle indicate that most arterial SMC are in the di- 
viding population and that the increased cell division 
rate results from shortening of the postmitotic, pre- 
DNA synthesis period (Gi and Go). By 3 days on the 
high fat-cholesterol diet serum cholesterol levels will 
have risen from approximately 100 mg% to 150-200. 
However, no increase in concentration of cholesterol in 
the arterial wall has been demonstrated before at least 
1-2 months. Also study by electron microscopy of 
SMC in mitosis at 3 days on diet shows no recognizable 
lipid droplets. Thus metabolic and cell kinetic changes 
in arterial SMC appear to antedate excessive accumula- 
tion of cholesterol. This apparent paradox has not yet 
been explained. 
INTRODUCTION 
We are investigating metabolic changes that 
take place in arteries of cholesterol-fed swine 
and other animals in the early stages of athero- 
genesis, including those that occur prior to the 
development of grossly visible atherosclerotic 
lesions. When young swine are fed atherogenic 
* Department of Pathology and Specialized Center of Research 
in Atherosclerosis, Albany Medical College, Albany, New York. 
diets such as those shown in Table I, they begin 
to develop grossly visible atherosclerotic lesions 
in the arch and in the distal portion of the ab- 
dominal aorta, as well as in the coronaries and 
other arteries, in approximately one month.^ ^ 
These lesions increase in size and number with 
time. The rate of increase appears to depend on 
the degree of hypercholesterolemia produced by 
the diet. Table II shows serum cholesterol levels 
associated with the various diets of Table I in a 
typical experiment. 
METHODS AND MATERIALS 
Most of the data presented are from experi- 
ments using the mild diet which produces serum 
cholesterol levels similar to those of young adult 
North Americans. On the mild diet atheroscler- 
otic lesions usually increase in number and size 
Table I. — Composition of diets consumed per day in 
grams 
'Stock" 
"Mild" 
"Severe" 
"Moderate" 
Ingredients 
(PS) 
(PSC) 
(TSC) 
(SO 
Casein 
143 
143 
95 
152 
Sucrose 
227 
227 
140 
224 
Butter 
57 
57 
87 
139 
Peanut oil 
57 
57 
87 
139 
Salt mix. Wesson 
30 
30 
30 
48 
Vitamin mix 
12.5 
12.5 
12.5 
20 
Choline Chloride 
2.5 
2.5 
2.5 
4 
Cellulose 
121 
113 
24.5 
41 
Cholesterol 
0 
8 
14 
22 
Sodium cholate 
0 
0 
7 
11 
Propylthiouracil 
0 
0 
0.5 
0 
Total 
650 
650 
500 
800 
Calories 
2,506 
2,506 
2,506 
4,006 
Table II. — Mean Serum cholesterol levels 
Initial 
90 mg% 
Final 
Stock diet group 
141 mg% 
Mild diet group 
185 mg% 
Severe diet group 
1525 mg% 
Moderate diet group 
480 mg% 
861 
