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 microvascular pathologies. These changes are not due to direct viral infection but may involve the receptor-mediated action of viral proteins, such as the envelope protein gp120. We sought to identify gp120 receptors which might mediate the vascular smooth muscle cell hyperplasia present 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 this activity. Rat aortic VSMCs were treated for 24 h with human (h)NPY and gp120 in the presence of 0.5% serum to measure [3H]thymidine incorporation, an index of cell proliferation. NPY increased [3H]thymidine incorporation by 80% after a 24-h treatment in a bimodal fashion, with peak effects at 10(-10) M and 10(-8) M. Gp120 was an even more potent mitogen for VSMCs with peak activity occurring at 10(-12) M. Peptide T was equipotent with gp120, and slightly less efficacious, suggesting 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 role for NPY receptors since antagonists of Y1 and Y2 subtypes substantially or completely inhibited gp120-mediated VSMC proliferation. This is the first demonstration of the proliferative effects of HIV viral protein gp120 on VSMCs. The effect appears to be mediated via gp120 sequences related to VIP, peptide T, and NPY. These ligands may be competitive inhibitors of binding or gp120 processing. Novel treatments may emerge based upon VIP and NPY receptor antagonists if further work substantiates a role for gp120 in the vascular abnormalities of AIDS.
Kim
J
J
Department of Physiology and Biophysics, Georgetown University Medical Center, Washington, DC, USA.
Ruff
M
M
Karwatowska-Prokopczuk
E
E
Hunt
L
L
Ji
H
H
Pert
C B
CB
Zukowska-Grojec
Z
Z
D000595:Amino Acid Sequence; D000818:Animals; D002318:Cardiovascular Diseases / Q000209:etiology* / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D006678:HIV / Q000235:genetics / Q000472:pathogenicity; D015699:HIV Envelope Protein gp120 / Q000235:genetics / Q000633:toxicity*; D015658:HIV Infections / Q000150:complications*; D006801:Humans; D006965:Hyperplasia; D008934:Mitogens / Q000494:pharmacology; D008969:Molecular Sequence Data; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000473:pathology*; D009478:Neuropeptide Y / Q000235:genetics / Q000494:pharmacology / Q000502:physiology; D015717:Peptide T / Q000235:genetics / Q000633:toxicity; D051381:Rats; D017476:Receptors, Neuropeptide Y / Q000187:drug effects* / Q000502:physiology*; D017386:Sequence Homology, Amino Acid; D014660:Vasoactive Intestinal Peptide / Q000235:genetics / Q000494:pharmacology / Q000502:physiology
D015699:HIV Envelope Protein gp120; D008934:Mitogens; D009478:Neuropeptide Y; D017476:Receptors, Neuropeptide Y; D015717:Peptide T; D014660:Vasoactive Intestinal Peptide