Parathyroid hormone-related protein antagonizes the action of parathyroid hormone on adult cardiomyocytes

Abstract

Ventricular cardiomyocytes have been identified as target cells for parathyroid hormone (PTH). A structurally related peptide hormone, parathyroid hormone-related peptide (PTH-rP), is expressed in the heart. In the present study, it was investigated whether PTH-rP can mimic or modify effects of PTH on cardiomyocytes. The investigated effect was induction of creatine kinase (CK) activity, which is associated with cardiac hypertrophy. PTH and PTH-rP have a similar secondary structure within the active domain 28-34, with exception of amino acid 29. At this position the hydrophilic glutamine in the PTH molecule corresponds to hydrophobic alanine in the PTH- rP molecule. Synthetic PTH or PTH-rP peptides covering domain 28-34 and recombinant full, length PTH(1-84) were used. PTH(28-48) (100 nM) induced CK activity within 24 h (123 ± 3%; means ± S.D., n = 4). PTH-rP(7-34) (1 nM to 1 μM) failed to induce CK activity in cardiomyocytes. Given simultaneously, PTH-rP (1 μM) reduced the stimulation of CK activity by PTH(1-84), PTH(1- 34), and PTH(28-48) by 94 ± 9, 79 ± 8, and 69 ± 14%, respectively (means ± S.D., n = 4). In contrast, PTH-rP(7-34) was sufficient to stimulate proliferation of chicken chondrocytes. Thus, PTH-rP exerts different effects on cardiomyocytes and classical target cells for PTH. A synthetic hybrid peptide was synthesized, [Ala29]PTH(28-48), in which alanine replaced glutamine at position 29, as in the PTH-rP molecule. In contrast to PTH(28- 48), this mutated peptide [Ala29]PTH(28-48) had no intrinsic activity but antagonized the effect of PTH(1-84) and PTH(28-48) on cardiomyocytes. The results demonstrate that on cardiomyocytes the effect of PTH can be antagonized by PTH-rP. This antagonism seems due to a hydrophobic replacement at position 29.