Effects of PTH-rP(107–111) and PTH-rP(7–34) on Adult Cardiomyocytes

Abstract

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) (1μm) 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.