HIV ENVELOPE PROTEIN GP120 INDUCES NEUROPEPTIDE-Y RECEPTOR-MEDIATED PROLIFERATION OF VASCULAR SMOOTH-MUSCLE CELLS - RELEVANCE TO AIDS CARDIOVASCULAR PATHOGENESIS

Hyperplasia of vascular smooth muscle cells (VSMCs) occurs during HIV infection, part of a spectrum of HIV-mediated cardiovascular and micro vascular pathologies. These changes are not due to direct viral infect ion but may involve the receptor-mediated action of viral proteins, su ch as the envelope protein gp120. We sought to identify gp120 receptor s which might mediate the vascular smooth muscle cell hyperplasia pres ent in HIV infection. A homology between neuropeptide Y (NPY) and the previously identified receptor-active V2-region of gp120 defined by an octapeptide sequence (Peptide T) related to VIP was noted. Since NPY is mitogenic for VSMCs we therefore determined whether gp120 shares th is activity. Rat aortic VSMCs were treated for 24 h with human (h)NPY and gp120 in the presence of 0.5% serum to measure [H-3]thymidine inco rporation, an index of cell proliferation. NPY increased [H-3]thymidin e incorporation by 80% after a 24-h treatment in a bimodal fashion, wi th peak effects at 10(-10) M and 10(-8) M. Gp120 was an even more pote nt mitogen for VSMCs with peak activity occurring at 10(-12) M. Peptid e T was equipotent with gp120, and slightly less efficacious, suggesti ng that this domain may mediate gp120 effects on VSMCs. When combined, gp120 and NPY acted to antagonize one another, lowering DNA synthesis to basal levels. The profile of pharmacologic inhibition supports a r ole for NPY receptors since antagonists of Y1 and Y2 subtypes substant ially or completely inhibited gp120-mediated VSMC proliferation. This is the first demonstration of the proliferative effects of HN viral pr otein gp120 on VSMCs. The effect appears to be mediated via gp120 sequ ences related to VIP, peptide T, and NPY. These ligands may be competi tive inhibitors of binding or gp120 processing. Novel treatments may e merge based upon VIP and NPY receptor antagonists if further work subs tantiates a role for gp120 in the vascular abnormalities of AIDS. (C) 1998 Published by Elsevier Science B.V. All rights reserved.