Direct actions of urotensin II on the heart: implications for cardiac fibrosis and hypertrophy.
Urotensin II (UII) is a somatostatin-like peptide recently identified as a potent vasoconstrictor. In this study, we examined whether UII promotes cardiac remodeling through nonhemodynamic effects on the myocardium. In a rat model of heart failure after myocardial infarction (MI), increased UII peptide and UII receptor protein expression was observed in both infarct and noninfarct regions of the left ventricle compared with sham. Moreover, post-MI remodeling was associated with a significant 75% increase in UII receptor gene expression in the heart (P<0.05 versus sham controls), with this increase noted in both regions of the left ventricle. In vitro, UII (10-7 mol/L) stimulation of neonatal cardiac fibroblasts increased the level of mRNA transcripts for procollagens alpha1(I), alpha1(III), and fibronectin by 139+/-15% (P<0.01), 59+/-5% (P<0.05), and 141+/-14% (P<0.01), respectively, with a concomitant 23+/-2% increase in collagen peptide synthesis as determined by 3H-proline incorporation (P<0.01). UII had no effect on cellular hypertrophy, as determined by changes in total protein content in isolated neonatal cardiomyocytes. However, expression of recombinant rat UII receptor in neonatal cardiomyocytes resulted in significant UII-dependent activation of hypertrophic signaling as demonstrated by increased total protein content (unstimulated, 122.4+/-4.0 microg/well; rat UII, 147.6+/-7.0 microg/well; P<0.01) and activation of the hypertrophic phenotype through Galpha(q)- and Ras-dependent pathways. These results indicate that, in addition to potent hemodynamic effects, UII may be implicated in myocardial fibrogenesis through increased collagen synthesis by cardiac fibroblasts and may also be an important determinant of pathological cardiac hypertrophy in conditions characterized by UII receptor upregulation.
Tzanidis
Alex
A
NHMRC Centre of Clinical Research Excellence in Therapeutics, Department of MedicineEpidemiology and Preventive Medicine, Monash University Medical School, Prahran, Victoria, Australia.
Hannan
Ross D
RD
Thomas
Walter G
WG
Onan
Döne
D
Autelitano
Dominic J
DJ
See
Fiona
F
Kelly
Darren J
DJ
Gilbert
Richard E
RE
Krum
Henry
H
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000831:Animals, Newborn; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D003094:Collagen / Q000096:biosynthesis; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005355:Fibrosis / Q000209:etiology / Q000473:pathology / Q000503:physiopathology*; D005786:Gene Expression Regulation; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology*; D006333:Heart Failure / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D006352:Heart Ventricles / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D006984:Hypertrophy / Q000209:etiology / Q000473:pathology / Q000503:physiopathology*; D007150:Immunohistochemistry; D009203:Myocardial Infarction / Q000150:complications; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled; D014162:Transfection; D014579:Urotensins / Q000378:metabolism / Q000494:pharmacology*
D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D014579:Urotensins; C473142:Uts2r protein, rat; D003094:Collagen; C029677:urotensin II