Effects of PTH-rP(107-111) and PTH-rP(7-34) on adult cardiomyocytes.
We investigated whether parathyroid hormone-related peptide (PTH-rP), recently found expressed in the heart, exerts growth and contractile effects on adult cardiomyocytes from rat hearts. Synthetic PTH-rP peptides were used covering either a protein kinase C (PKC)-activating domain [PTH-rP(107-111)], or an adenylate cyclase activating domain [PTH-rP(1-34) and PTH-rP(7-34)]. PTH-rP(107-111) (1 micro M) increased creatine kinase BB activity (CK-BB), a CK isoform re-expressed during cardiac hypertrophy, within 24 h by 62+/-12%. This induction was abolished in the presence of the mitogen-activated-protein (MAP)-kinase-kinase inhibitor PD 98059. PTH-rP(107-111) activated p42-MAP-kinase within 15 min, increased protein synthesis (19+/- 4%), total protein mass (19+/-5%), cell volume (45+/-7%), and cross-sectional area (38+/-9%) of cardiomyocytes. Activation of p42-MAP-kinase and increase in protein synthesis were abolished in presence of bisindolylmaleimide, a PKC inhibitor. PTH- rP(107-111) did not directly influence contractile activity but reduced the contractile response to isoprenaline. In contrast, PTH-rP(1-34) and PTH-rP(7-34) induced spontaneous contractile activity in 3-day-old cultures. This induction was abolished in presence of Rp-cAMPS, a protein kinase A inhibitor, indicating an involvement of cAMP in this response. PTH-rP(1-34) also increased the cellular accumulation of cAMP. It is concluded that PTH-rP exert direct effects on adult cardiomyocytes by activating either PKC via a functional domain covered by amino acids 107-111 or by activation of cAMP-dependent protein kinase via a functional domain covered by amino acids 7-34. Since these parts of PTH-rP have either no homology [PTH-rP(107-111)] or only a limited structural similarity [PTH-rP(7-34)] to parathyroid hormone, these activities of PTH-rP have to be clearly distinguished from those described for parathyroid hormone.
Schlüter
K D
KD
Physiologisches Institut, Justus-Liebig-Universität, Giessen, Germany.
Weber
M
M
Piper
H M
HM
D000818:Animals; D002478:Cells, Cultured; D006321:Heart / Q000187:drug effects*; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000166:cytology; D044162:Parathyroid Hormone-Related Protein; D010446:Peptide Fragments / Q000494:pharmacology*; D011506:Proteins / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
D044162:Parathyroid Hormone-Related Protein; D010446:Peptide Fragments; D011506:Proteins; C071784:parathyroid hormone-related protein (107-111); C431128:parathyroid hormone-related protein (7-34)