Hsp90 activates eNOS in vasculature. we investigated basal and agonist evoked eNOS dependent relaxations and the role of hsp90 on these endothelial relaxations in hypercholesterolemia, since it is not studied well.
Rabbits were fed with a regular/high cholesterol diet (%2) for 6 weeks. Hypercholesterolemia almost totally abolished agonist evoked eNOS dependent KCl-ACh relaxations (93,9 % inhibition), however inhibited phenylephrine-ACh relaxations only by 32,8 % in aorta in krebs buffer with indomethacine suggesting increased EDHF responses in hypercholesterolemic aorta.
Basal eNOS dependent LNA-induced further contraction and papaverin-induced relaxations were not changed in hypercholesterolemic aorta.
Hsp90 inhibitor radicicol (10 μg/ml) for 15 hrs decreased ACh relaxation after pre-contraction with KCl (11,22±1,18 vs 7,33±1,58 *p<0,01 student t test, n=5) however did not cause any further inhibition in hypercholesterolemic aorta, suggesting that hsp90 inhibitors do not cause any further inhibition since hsp90 dependent eNOS activation may be already disrupted in hypercholesterolemia.
We concluded that although basal eNOS dependent relaxations were not affected, since the agonist evoked eNOS relaxations were decreased which seems mainly depend on hsp90, a compansotory increase in EDHF relaxations may develop in hypercholesterolemic aorta.