Serotonin, which is released when platelets aggregate at carotid lesions, may contribute to cerebral ischemia. Our goal was to test the hypothesis that dietary treatment of atherosclerosis reverses the augmented cerebral vasoconstrictor response to serotonin. We studied normal cynomolgus monkeys, atherosclerotic monkeys, and atherosclerotic monkeys that were fed a normal (regression) diet for 18 months. Morphometric studies indicated that the regression diet reduced intimal area in the carotid arteries by about 50-75%. Cerebral blood flow was measured with microspheres, and microvascular pressure was measured with a micropipette in pial arteries that were approximately 300 micron in diameter. Values for cerebral blood flow and arteriolar pressure were used to calculate resistance of large cerebral arteries (greater than 300 micron diameter). Infusion of serotonin produced a modest increase in the resistance of large cerebral arteries in normal monkeys. Vasoconstrictor responses to serotonin were increased more than fivefold in atherosclerotic monkeys. The major finding of the study is that dietary treatment of atherosclerosis abolishes augmented cerebral responses to serotonin.

Animals↗

PubMedDate not supplied

Structural characterization of a 14-residue peptide ligand of the retinoblastoma protein: comparison with a nonbinding analog.

The retinoblastoma protein, a 110-kDa nuclear anti-oncoprotein, complexes specifically with transforming proteins of several oncogenic DNA viruses. A peptide [NLFCSEEMPSSDDE] derived from one of the viral proteins (simian virus 40 large T antigen) is known to competitively bind retinoblastoma protein, but a mutant analog [NLFCSKEMPSSDDE] does not. We studied the T peptide with HPLC to determine whether it can dimerize, and we employed circular dichroism spectroscopy to determine whether both peptides can exist in stable secondary structural conformations. HPLC analyses revealed that the T peptide is subject to oxidation and readily dimerizes. Circular dichroism analyses showed that both peptides can be induced to form stable secondary structural conformations under conditions that stabilize intramolecular hydrogen bonding in short peptides (90% 2,2,2-trifluoroethanol; 4 degrees C). The circular dichroism spectra of both peptide species were similar except for a statistically significant difference in the contour near 210 nm. Spectral analysis of the T-derived peptide species predicted elements of alpha-helix (18%), antiparallel beta-sheet (21%), beta-turn (22%) and unordered conformations (41%). An analysis of the mutant peptide species also predicted elements of alpha-helix (8%), antiparallel beta-sheet (28%), beta-turn (22%) and unordered conformations (40%). Thus, a small difference in the stabilized secondary structural conformations of the two sets of peptide species might partly explain their differential binding affinities for retinoblastoma protein, but it is likely that electrostatic charge differences resulting from the glutamic acid to lysine substitution play a dominant role.

Amino Acid Sequence↗