title: NPY1-36 and PYY1-36 activate cardiac fibroblasts: an effect enhanced by genetic hypertension and inhibition of dipeptidyl peptidase 4.
abstract: Cardiac sympathetic nerves release neuropeptide Y (NPY)1-36, and peptide YY (PYY)1-36 is a circulating peptide; therefore, these PP-fold peptides could affect cardiac fibroblasts (CFs). We examined the effects of NPY1-36 and PYY1-36 on the proliferation of and collagen production ([(3)H]proline incorporation) by CFs isolated from Wistar-Kyoto (WKY) normotensive rats and spontaneously hypertensive rats (SHRs). Experiments were performed with and without sitagliptin, an inhibitor of dipeptidyl peptidase 4 [DPP4; an ectoenzyme that metabolizes NPY1-36 and PYY1-36 (Y1 receptor agonists) to NPY3-36 and PYY3-36 (inactive at Y1 receptors), respectively]. NPY1-36 and PYY1-36, but not NPY3-36 or PYY3-36, stimulated proliferation of CFs, and these effects were more potent than ANG II, enhanced by sitagliptin, blocked by BIBP3226 (Y1 receptor antagonist), and greater in SHR CFs. SHR CF membranes expressed more receptor for activated C kinase (RACK)1 [which scaffolds the Gi/phospholipase C (PLC)/PKC pathway] compared with WKY CF membranes. RACK1 knockdown (short hairpin RNA) and inhibition of Gi (pertussis toxin), PLC (U73122), and PKC (GF109203X) blocked the proliferative effects of NPY1-36. NPY1-36 and PYY1-36 stimulated collagen production more potently than did ANG II, and this was enhanced by sitagliptin and greater in SHR CFs. In conclusion, 1) NPY1-36 and PYY1-36, via the Y1 receptor/Gi/PLC/PKC pathway, activate CFs, and this pathway is enhanced in SHR CFs due to increased localization of RACK1 in membranes; and 2) DPP4 inhibition enhances the effects of NPY1-36 and PYY1-36 on CFs, likely by inhibiting the metabolism of NPY1-36 and PYY1-36. The implications are that endogenous NPY1-36 and PYY1-36 could adversely affect cardiac structure/function by activating CFs, and this may be exacerbated in genetic hypertension and by DPP4 inhibitors.
authors.affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Xiao
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Delbert G
authors.initials: DG
authors.lastname: Gillespie
authors.affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania edj@pitt.edu.
authors.forename: Edwin K
authors.initials: EK
authors.lastname: Jackson
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects*; D003094:Collagen / Q000096:biosynthesis / Q000187:drug effects*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology*; D004963:Estrenes / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000378:metabolism; D006973:Hypertension / Q000235:genetics*; D007211:Indoles / Q000494:pharmacology; D008301:Maleimides / Q000494:pharmacology; D009206:Myocardium / Q000166:cytology; D009478:Neuropeptide Y / Q000494:pharmacology*; D010446:Peptide Fragments / Q000494:pharmacology; D019894:Peptide YY / Q000494:pharmacology*; D037342:Pertussis Toxin / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D011760:Pyrrolidinones / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D000075370:Receptors for Activated C Kinase; D015398:Signal Transduction; D000068900:Sitagliptin Phosphate / Q000494:pharmacology*; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D004963:Estrenes; D007211:Indoles; D008301:Maleimides; D009478:Neuropeptide Y; D010446:Peptide Fragments; D011760:Pyrrolidinones; C550931:RACK1 protein, rat; D000075370:Receptors for Activated C Kinase; D019894:Peptide YY; D000804:Angiotensin II; C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione; D003094:Collagen; D037342:Pertussis Toxin; D011493:Protein Kinase C; D010738:Type C Phospholipases; D019204:GTP-Binding Proteins; C070515:bisindolylmaleimide I; C514549:peptide YY (1-36); D000068900:Sitagliptin Phosphate
keywords: cardiac fibroblasts; cell proliferation; dipeptidyl peptidase 4; neuropeptide Y1–36; peptide YY1–36; receptor for activated C kinase 1; spontaneously hypertensive rats