title: Role of RACK1 in the differential proliferative effects of neuropeptide Y(1-36) and peptide YY(1-36) in SHR vs. WKY preglomerular vascular smooth muscle cells.
abstract: Previous studies show that neuropeptide Y(1-36) (NPY(1-36)) and peptide YY(1-36) (PYY(1-36)), by engaging Y1 receptors, stimulate proliferation of spontaneous hypertensive rat (SHR) preglomerular vascular smooth muscle cells (PGVSMCs). In contrast, these peptides have little effect on proliferation of Wistar-Kyoto (WKY) PGVSMCs. Why SHR and WKY PGVSMCs differ in this regard is unknown. Because receptor for activated C kinase 1 (RACK1) can modulate cell proliferation, we tested the hypothesis that differences in RACK1 levels/localization may explain the differential response of SHR vs. WKY PGVSMCs to NPY(1-36) and PYY(1-36). Western blotting for RACK1 in subcellular fractions of cultured SHR and WKY PGVSMCs demonstrated increased levels of RACK1 in the membrane and cytoskeletal subcellular fractions of SHR vs. WKY PGVSMCs. NPY(1-36) and PYY(1-36) stimulated proliferation of SHR PGVSMCs, and siRNA knockdown of RACK1 abrogated this effect. Neither NPY(1-36) nor PYY(1-36) stimulated the proliferation of WKY PGVSMCs. However, in WKY PGVSMCs treated with a RACK1 plasmid, both NPY(1-36) and PYY(1-36) stimulated proliferation. In SHR PGVSMCs, inhibitors of the G(i)/phospholipase C/PKC pathway (a pathway known to be organized by RACK1) attenuated the ability of NPY(1-36) to stimulate the proliferation of SHR PGVSMCs. Our results suggest that RACK1 modulates the ability of PGVSMCs to respond to the proliferative actions of NPY(1-36) and PYY(1-36)and differences in RACK1 levels/localization account for, in part, differential proliferative responses to NPY(1-36) and PYY(1-36) in SHR vs. WKY PGVSMCs. Because dipeptidyl peptidase IV inhibitors increase NPY(1-36) and PYY(1-36) levels, our findings have implications for the use of such drugs in diabetic patients.
authors.affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219, USA.
authors.forename: Dongmei
authors.initials: D
authors.lastname: Cheng
authors.forename: Xiao
authors.initials: X
authors.lastname: Zhu
authors.forename: Delbert G
authors.initials: DG
authors.lastname: Gillespie
authors.forename: Edwin K
authors.initials: EK
authors.lastname: Jackson
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D019204:GTP-Binding Proteins / Q000378:metabolism*; D020962:Heterotrimeric GTP-Binding Proteins / Q000378:metabolism; D007668:Kidney / Q000098:blood supply*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000502:physiology; D032389:Myocytes, Smooth Muscle / Q000502:physiology*; D009478:Neuropeptide Y / Q000502:physiology*; D019894:Peptide YY / Q000502:physiology*; D010957:Plasmids; D011493:Protein Kinase C / Q000378:metabolism; D034741:RNA, Small Interfering; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D000075370:Receptors for Activated C Kinase; D015398:Signal Transduction; D013936:Thymidine / Q000378:metabolism; D014316:Tritium / Q000032:analysis; D010738:Type C Phospholipases / Q000378:metabolism
chemical_list: D009478:Neuropeptide Y; C550931:RACK1 protein, rat; D034741:RNA, Small Interfering; D000075370:Receptors for Activated C Kinase; D014316:Tritium; D019894:Peptide YY; D011493:Protein Kinase C; D010738:Type C Phospholipases; D019204:GTP-Binding Proteins; D020962:Heterotrimeric GTP-Binding Proteins; D013936:Thymidine