The Effect of Pravastatin on Expression of Platelet-Derived Endothelial Nitric Oxide Synthase(eNOS) m-RNA and Atherosclerosis Course in Rabbits.

Objective

To observe changes of platelet-derived endothelial nitric oxide synthesase(eNOS) mRNA expression in hypercholesterolemia( HC) and atherosclerosis( AS) rabbits, and relationship between these changes and atherosclerosis regression and reversion. To probe into mechanism of pravastatin on preventing and improving pathological courses of AS.

Methods

30 male New Zealand White rabbits were divided randomly into three groups, 12 in group A, 12 in group B, and 6 in group C. All of them were fed with cholesterol-riched food (1g cholesterol,10g pig fat) daily during the first 12 weeks. In addition, in group A, pravastatin (10mg) was orally administered daily. At end of the 12^th week, 6 of in group A and B were killed randomly and their aortas were removed and pathologic changes were studied, such as thickness of fatty-streaks or atherosclerotic plaques. In following 12 weeks, food enriched with cholesterol was stopped and substituted with normal food in all three groups. Treatment with pravastatin was continued in remaining members of group A. Pravastatin TX was initiated in remaining members of group B. No additional medicine was given to group C. At end 24^th week, all of rabbits were killed and their aortas were examined for same pathologic changes as above. The expression of eNOS mRNA, NO, the activity of NOS and the level of serum lipids were measured at different times (0 week, 12^th week and 24^th week).

Results

1. The expressions of platelet-derived eNOS mRNA(2–4×10⁸ platelet /ml)

The expressions in group A were 0.739±0.364,0.992±0.539,0.1.019±0.280 at 0, 12^th, 24^thweeks, respectively (difference not significant).The expressions in group B were 0.952±0.768,0.490±0.245,1.00±0.774 (reduced significantly at 12 week compared with 0 week(P<0.01), but increased at 24th week compared with 12th week(P<0.05). The expression in group C were 0.816±0.163,0.327±0.285,0.186±0.117 (reduced at 12th week and 24th week compared with 0 week(P<0.05 and P<0.01).It was reduced in B group and C group compared with group A at 12 week(P<0.05) and was increased in A group and B group compared with C group at 24 week(P<0.01).

2. Pathologic appearances of the arteries

In group A, the intima was smooth and glossy in all of aortas at the 12^th and 24^th weeks. While in group B, there were a lot of yellow-gray fatty-streaks in tentire intima of all large arteries at the 12^th week. The fatty-streaks in ascending aorta, aorta arch and thoracic aorta were thicker and larger than those in abdominal aorta and common iliac arteries. There were annular plaques at opening of coronary arteries and common carotid arteries, bulgied into the cavity at the 24^th week. In group C, there were marked plaques in entire aorta at the 24^th week.

3. Microscopic features

The fatty-streaks or atherosclerotic plaques thicken measured in percentage of vessel wall, were 0.035±0.023,0.325±0.175,0.765±0.143 at 0,12^th,24^th_, respectively. Greater in group C compared with group A and group B at 24 week(P<0.01).

Conclusions

The down-regulated expression of platelet-derived eNOS mRNA in HC or AS rabbits might be one of important causes in initiation and development of AS. Pravastatin can up-regulate expression of platelet-derived eNOS mRNA and NOS activity, and maintain normal production of NO. This leads to improvement of pathologic appearances or microscopic features of AS.