Induction of hypertrophic responsiveness of cardiomyocytes to neuropeptide Y in response to pressure overload.
To determine whether neuropeptide Y (NPY)-related mechanisms become activated with progression of cardiac hypertrophy in vivo, protein mass and de novo protein synthesis (incorporation of [(14)C]Phe, 0.1 muCi ml(-1)) were assessed in cardiomyocytes, obtained from spontaneously hypertensive rats (SHRs) and normotensive Wistar Kyoto rats (8, 12, 16, 20, and 24 weeks of age), and cultured for 24 h. NPY (10(-8) M) increased protein mass of cardiomyocytes from 16-week-old SHRs by 9.2 +/- 2.1% (n = 8, P < 0.05). De novo protein synthesis was increased maximally in SHRs at 12, 16, and 20 weeks (P < 0.05, n = 8) in response to NPY by 12.6 +/- 2.1% (10(-6) M), 20.1 +/- 4.2% (10(-8) M), and 9.4 +/- 1.8% (10(-7) M), respectively. Peptide YY(3-36), (PYY(3-36)), which displays selectivity for NPY Y(2) and NPY Y(5) receptors, and the NPY Y(5)-selective agonist [D-Trp(34)]-NPY increased de novo protein synthesis maximally by 16.2 +/- 5.1% (10(-7) M; n = 4, P < 0.05) and 17.8 +/- 5.2% (10(-6) M; n = 7, P < 0.05), respectively, in SHRs at 16 weeks, whereas [Leu(31)Pro(34)]-NPY (< or =10(-6) M), which displays some activity at NPY Y(1) and NPY Y(4) receptors, did not. The NPY Y(1)-selective antagonist BVD-42 (2 x 10(-7) M) and the NPY Y(2)-selective antagonist BIIE0246 (2 x 10(-7) M) did not attenuate responses to NPY (10(-7) M) and PPY(3-36) (10(-7) M). These data indicate that hypertrophic responsiveness to NPY, mediated via NPY Y(5) receptors, is induced transiently in SHR cardiomyocytes subsequent to onset of cardiomyocyte hypertrophy in response to pressure overload.
Bell
David
D
Department of Therapeutics and Pharmacology, Centre for Cardiovascular and Genetics Research, School of Medicine, The Queen's University of Belfast, Whitla Medical Building, 97 Lisburn Road, Belfast BT9 7BL, Northern Ireland, UK. d.bell@qub.ac.uk
Allen
Adrian R
AR
Kelso
Elizabeth J
EJ
Balasubramaniam
Ambikaipakan
A
McDermott
Barbara J
BJ
D000818:Animals; D006332:Cardiomegaly / Q000473:pathology*; D004247:DNA / Q000096:biosynthesis; D005260:Female; D006321:Heart / Q000187:drug effects*; D006801:Humans; D006973:Hypertension / Q000473:pathology*; D008297:Male; D009124:Muscle Proteins / Q000096:biosynthesis / Q000235:genetics; D009206:Myocardium / Q000166:cytology / Q000473:pathology*; D009478:Neuropeptide Y / Q000494:pharmacology*; D010649:Phenylalanine / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D017476:Receptors, Neuropeptide Y / Q000819:agonists / Q000037:antagonists & inhibitors; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000494:pharmacology
D009124:Muscle Proteins; D009478:Neuropeptide Y; D017476:Receptors, Neuropeptide Y; D016212:Transforming Growth Factor beta; C100568:neuropeptide Y5 receptor; D010649:Phenylalanine; D004247:DNA