Peroxynitrite-modified 99mTc-β-VLDL: tissue distribution and plasma clearance rate

Abstract

Free radicals superoxide (O 2 −) and nitric oxide ( •NO) are generated by blood vessels and can rapidly react to produce a peroxynitrite anion (ONOO −), a powerful oxidant that modifies lipoproteins making them more atherogenic. The aim of this study was to investigate the effect of peroxynitrite-induced modifications on β-very-low-density lipoprotein (β-VLDL) as to its biodistribution and plasma clearance rate, as well as the uptake of these particles by THP-1 cells. After being injected into New Zealand White rabbits, the peroxynitrite-modified β-VLDL ( 99mTc-per-β-VLDL) was cleared from circulation faster than the native β-VLDL ( 99mTc-nat-β-VLDL) in both normocholesterolemic rabbits (NC) and in hypercholesterolemic rabbits (HC). In HC rabbits, the fractional clearance of 99mTc-labeled β-VLDL was significantly lower than in NC rabbits. The in vivo studies showed that accumulation of 99mTc-labeled β-VLDL, expressed per gram of tissue, followed the decreasing order: kidney > liver > spleen > adrenal gland ≥ lung > aortic arch > heart ≥ abdominal aorta > thoracic aorta > psoas muscle. The high accumulation in the kidneys suggests the processing of 99mTc-labeled apolipoproteins by receptors present in kidney cells. The accumulation of 99mTc-nat-β-VLDL in the whole organ was the following: liver > kidney > heart > spleen > adrenal gland > aorta in HC and NC rabbits. The uptake of 99mTc-per-β-VLDL by the spleen was greater than the uptake by the heart in both groups. The in vitro studies showed that the uptake of 99mTc-per-β-VLDL by THP-1 cells was higher than that of 99mTc-nat-β-VLDL. These results show that peroxynitrite-modified β-VLDL is rapidly removed from plasma and accumulates in several tissues, mainly in the liver and kidney. This may be particularly important in hypercholesterolemic situations that could favor the accumulation of native and peroxynitrite-modified β-VLDL in several tissues.